Benzoic acid intermediates to 4-benzoylisoxazole herbicides

ABSTRACT

Compound of the formula                    
     are useful as intermediates to new 4-benzoylisoxazoles.

This application is a divisional of U.S. patent application Ser. No.08/858,578, filed May 19, 1997 now U.S. Pat. No. 5,998,653, now allowed,which is divisional of U.S. patent application Ser. No. 08/663,048,filed Sep. 6, 1996, now U.S. Pat. No. 5,658,858, which is the U.S.national phase of International Application No. PCT/EP94/04051, filedDec. 6, 1994. Patent application Ser. No. 08/663,048 is incorporated byreference herein in its entirety and relied upon.

FIELD OF THE INVENTION

This invention relates to novel 4-benzoylisoxazole derivatives,compositions containing them, processes for their preparation,intermediates in their preparation and their use as herbicides.

BACKGROUND ART

Herbicidal 4-benzoylisoxazoles are described in European PatentPublication Numbers 0418175, 0487357, 0527036, 0527037, 0560482, and0560483.

DESCRIPTION OF THE INVENTION

The present invention provides 4-benzoylisoxazole derivatives of formula(I):

wherein:

R represents the hydrogen atom or a group —CO₂R⁴;

R¹ represents:

a straight- or branched-chain alkyl group containing up to six halogenatoms; or

a cycloalkyl group containing from three to six carbon atoms optionallysubstituted by one or more R⁵ groups or one or more halogen atoms;

R² represents:

a halogen atom;

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

a straight- or branched-chain alkyl group containing up to six carbonatoms which is substituted by one or more groups —OR⁵; or

a group selected from nitro, cyano, —CO₂R⁵, —S(O)_(p)R⁶′,—O(CH₂)_(m)OR⁵, —COR⁵, —NR⁵R⁶, —N(R⁸)SO₂R⁷, —OR⁵, —OSO₂R⁷,—(CR⁹R¹⁰)_(t)SO_(q)R⁷ and —CONR⁵R⁶;

R³ represents a group —C(Z)═Y;

in which Y═O or S (preferably Y represents O);

Z represents a group R⁶³, —NR⁶⁰R⁶¹, —N(R⁶⁰)—NR⁶¹R⁶², —SR⁶³, —OR⁶³;wherein R⁶⁰, R⁶¹ and R⁶² which may be the same or different eachrepresents:

a hydrogen atom, a straight- or branched-chain alkyl, alkenyl or alkynylgroup containing up to six carbon atoms optionally substituted by one ormore halogen atoms; or a group —(CH₂)_(w)— [phenyl optionallysubstituted by one to five groups R²¹];

R⁶³ represents:

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms, or a group —(CH₂)_(w)—[phenyl optionally substituted by one tofive groups R²¹];

X represents a group —N(R⁸′)—; in which,

R⁸ represents:

the hydrogen atom;

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to ten carbon atoms optionally substituted by one or more halogenatoms;

a cycloalkyl group containing from three to six carbon atoms;

—(CH₂)_(w)—[phenyl optionally substituted by from one to five groupsR²¹]; or

a group —OR¹¹;

and the groups R³ and R⁸′ in the grouping of formula —N(R⁸′)—R³ may,together with the nitrogen atom to which they are attached, form a 4 to6 membered ring of formula (AA), (AB), (AC) or (AD):

wherein

E represents an alkylene or alkylidene chain of 1 or 3 carbon atomsoptionally substituted by a group R⁶⁴ and E¹ represents alkyl of 1 or 2carbon atoms optionally substituted by a group R⁶⁴, wherein R⁶⁴represents an optionally halogenated straight- or branched-chain alkylgroup containing up to 6 carbon atoms and R⁶⁵ represents the hydrogenatom or an optionally halogenated straight- or branched-chain alkylgroup containing up to 6 carbon atoms; in formula (AB) the groups Y maybe the same or different;

n represents zero or an integer from one to four; where n is greaterthan one the groups R² may be the same or different;

R⁴ represents a straight- or branched-chain alkyl group containing up tosix carbon atoms optionally substituted by one or more halogen atoms;.

R⁵ and R⁶, which may be the same or different, each represents:

the hydrogen atom,

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

R⁶′ is as hereinbefore defined for R⁶ but excluding the hydrogen atom;

R⁷ represents:

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

a cycloalkyl group containing from three to six carbon atoms;

a group —(CH₂)_(w)—[phenyl optionally substituted by from one to fivegroups R²¹];

R⁸ is as hereinbefore defined for R⁸′;

R⁹ and R¹⁰ represent a group selected from:

the hydrogen atom;

a straight- or branched-chain alkyl group containing up to six(preferably up to 3) carbon atoms optionally substituted by one or morehalogen atoms;

R¹¹ represents a straight- or branched-chain alkyl group containing upto six carbon atoms optionally substituted by one or more halogen atoms;

R²¹ represents:

a halogen atom;

a straight- or branched-chain alkyl group containing up to three carbonatoms optionally substituted by one or more halogen atoms;

or a group selected from nitro, cyano, —S(O)_(p)R⁵′ and —OR⁵;

wherein R⁵′ is as hereinbefore defined for R⁵ but excluding the hydrogenatom;

m represents one, two or three;

p represents zero, one or two;

q represents zero, one or two;

t represents one, two, three or four (preferably one); and

w represents zero or one;

and agriculturally acceptable salts thereof, which possess valuableherbicidal properties.

Furthermore in certain cases the groups R, R¹, R² and others may giverise to geometric and/or optical isomers. All such forms are embraced bythe present invention

By the term “agriculturally acceptable salts” is meant salts the cationsor anions of which are known and accepted in the art for the formationof salts for agricultural or horticultural use. Preferably the salts arewater-soluble.

The compounds of the invention, in some aspects of their activity, forexample in their control of important weeds found in cereal crops, e.g.Galium aparine, Alopecurus myosuroides and Avena fatua (especiallyGalium aparine), and in their selectivity in important cereal crops,e.g. wheat and maize, show advantages over known compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds are of particular interest against monocotyledonous weedsby post-emergence application.

Preferably the 2-position of the benzoyl ring is substituted, mostpreferably by the group —XR³.

Preferably the 5- and 6-positions of the benzoyl ring are unsubstituted.

Preferred compounds of formula (I) are those wherein:

R¹ represents:

a straight- or branched-chain alkyl group containing up to six carbonatoms which is optionally substituted by one or more halogen atoms; or

a cycloalkyl group containing from three to six carbon atoms optionallysubstituted by one or more methyl groups or one or more halogen atoms;

R² represents:

a halogen atom;

a straight- or branched-chain alkyl, alkenyl or alkynyl group containingup to six carbon atoms optionally substituted by one or more halogenatoms;

a straight- or branched-chain alkyl group containing up to six carbonatoms which is substituted by a group —OR⁵; or

a group selected from nitro, cyano, —CO₂R⁵, —S(O)_(p)R⁶′,—O(CH₂)_(m)OR⁵, —COR⁵, —NR⁸SO₂R₇, —OR⁵, —CH₂SO_(q)R⁷;

X represents a group —N(R⁸′)—; or the groups R³ and R⁸′ in the groupingof formula —N(R⁸′)—R³, together with the nitrogen atom to which they areattached, form a ring of formula (AB) above;

Z represents a group R⁶³, —NR⁶⁰R⁶¹, —SR⁶³ or —OR⁶³; and

n represents zero, one, two or three.

A further preferred class of compounds of formula (I) are those wherein:

R¹ represents:

methyl ethyl i-propyl, cyclopropyl or 1-methylcyclopropyl;

R² represents:

a halogen atom;

a straight- or branched-chain alkyl or alkenyl group containing up tofour carbon atoms optionally substituted by one or more halogen atoms;or

a group selected from —COR⁵, —CO₂R⁵, —S(O)_(p)R⁶′, —CH₂SO_(q)R⁷,—O(CH₂)_(m)OR⁵, —OR⁵ and —NR⁸SO₂R⁷;

R⁵ and R⁶′, which may be the same or different, each represents:

a straight- or branched-chain alkyl group containing up to three carbonatoms optionally substituted by one or more halogen atoms;

R⁷ represents:

a straight- or branched-chain alkyl group containing up to four carbonatoms optionally substituted by one or more halogen atoms;

R⁸ represents:

the hydrogen atom or a straight- or branched-chain alkyl groupcontaining up to four carbon atoms optionally substituted by one or morehalogen atoms;

m represents two or three;

q represents zero, one or two;

n represents zero, one or two;

R⁸′ represents hydrogen or a straight- or branched-chain alkyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms;

Y represents oxygen;

Z represents R⁶³ or —OR⁶³;

in which R⁶³ represents a straight- or branched-chain alkyl groupcontaining up to six carbon atoms optionally substituted by one or morehalogen atoms; and

—OR⁶³ represents a straight- or branched-chain alkoxy, alkenyloxy oralkynyloxy group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms.

A further preferred class of compounds of formula I are those wherein:

R represents hydrogen or —CO₂R⁴ wherein R⁴ is ethyl;

R¹ represents:

methyl, ethyl, i-propyl, cyclopropyl, or 1-methylcyclopropyl;

R² represents:

a halogen atom;

a straight- or branched-chain alkyl group containing up to four carbonatoms optionally substituted by one or more halogen atoms; or

a group —OR⁵ or —S(O)_(p)R⁶′;

in which R⁵ and R⁶′, which may be the same or different, eachrepresents:

a straight- or branched-chain alkyl group containing up to three carbonatoms optionally substituted by one or more halogen atoms;

Y represents oxygen;

Z represents:

a group R⁶³ or —OR⁶³; in which R⁶³ represents a straight- orbranched-chain alkyl group containing up to six carbon atoms optionallysubstituted by one or more halogen atoms; and

n represents zero, one or two.

A further preferred class of compounds of formula I are those wherein:

R represents hydrogen or —CO₂Et;

R¹ represents cyclopropyl or isopropyl;

R² represents halogen, —OR⁵, —CF₃, methyl or —S(O)_(p)Me;

R⁸′ represents a straight- or branched-chain alkyl or alkenyl groupcontaining up to four carbon atoms;

Y represents oxygen;

Z represents R⁶³, —SR⁶³ or —OR⁶³;

R⁶³ represents:

a straight- or branched-chain alkyl group containing up to four carbonatoms optionally substituted by one or more halogen atoms;

or phenyl;

R⁵ represents alkyl containing one or two carbon atoms optionallysubstituted by one or more halogen atoms;

n represents zero, one or two; and

p represents zero, one or two.

A further preferred class of compounds of formula I are those wherein:

R represents hydrogen;

R¹ represents cyclopropyl;

R² represents halogen;

R⁸′ represents a straight- or branched-chain alkyl group of one to fourcarbon atoms;

Y represents oxygen;

Z represents R⁶³ or R⁶³;

in which R⁶³ represents a straight- or branched-chain alkyl groupcontaining up to four carbon atoms optionally substituted by one or morehalogen atoms; and

n represents one or two.

Particularly important compounds of formula (I) include the following:

1. 4-[4-chloro-2-(N-methylacetamido)benzoyl]-5-cyclopropylisoxazole;

2.4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

3.4-[3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

4.4-[3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

5.4-[3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

6.4-[4-bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

7.4-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)benzoyl]-5-cyclopropylisoxazole;

8.4-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxybenzoyl]-5-cyclopropylisoxazole;

9.4-[3,4-dichloro-2-(N-propyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

10.4-(3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

11.4-[3,4-dichloro-2-(N-alkyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

12.4-[3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

13.4-[3,4dichloro-2-(N-ethyl-N-propyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

14.4-[3,4dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

15.4-[3,4chloro-2-(N-ethyl-N-n-butyloxycarbonylamino)benzoyl]-5cyclopropylisoxazole;

16.4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-isopropylisoxazole;

17.4-[4-bromo-3-ethoxy-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

18.4-[4chloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

19.5-cyclopropyl-4-[3,4-difluoro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole;

20.4-[4-chloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

21.4-[4-chloro-2-(N-propyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

22.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-fluorobenzoyl]isoxazole;

23.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole;

24.5-cyclopropyl-4-[2-(N-ethyl-N-ethoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole;

25.5-cyclopropyl-4-[2-(N-ethyl-N-isopropyloxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole;

26.5-cyclopropyl-4-[2-(N-methyl-N-methoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole;

27.4-[4-bromo-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

28.5-cyclopropyl-4-[4-iodo-2-(N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole;

29.5-cyclopropyl-4-[2-(N-methyl-N-methoxycarbonylamino)-4-trifluoromethoxybenzoyl]isoxazole;

30.4-[4-chloro-2-(N-isobutyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole,

31.4-[3,4-dichloro-2-(N-methyl-N-methylthiocarbonylamino)benzoyl]-5-cyclopropylisoxazole;

32.5-cyclopropyl-4-[4-methyl-2-(N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole;

33.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-methylsulphonylbenzoyl]isoxazole;

34.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)benzoyl]isoxazole;

35.4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-(methylthio)benzoyl]-5-cyclopropylisoxazole;

36.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3,4-difluorobenzoyl]isoxazole;

37.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-(methylthio)benzoyl]isoxazole;

38.4-[4-chloro-2-(N-ethyl-N-methoxycarbonylamino)-3-fluorobenzoyl]-5-cyclopropylisoxazole;

39.4-[3,4-dibromo-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5cyclopropylisoxazole;

40.4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

41.5-cyclopropyl-4-[2-(N-ethyl-N-phenoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole;

42.4-[4-chloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

43.4-[4-chloro-2-(N-propyl-N-propyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

44.4-[4-chloro-2-(N-propyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

45.4-[4-chloro-2-(N-propyl-N-n-butyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole;

46. ethyl4-[3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole-3-carboxylate;

47. ethyl4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole-3-carboxylate;

48.4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole;

49.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-methylsulphonylbenzoyl]isoxazole;and

50.5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-methylsulphinylbenzoyl]isoxazole.

The numbers 1 to 50 are assigned to these compounds for reference andidentification hereinafter.

Compounds of formula (I) may be prepared by the application oradaptation of known methods (i.e. methods heretofore used or describedin the literature), for example as hereinafter described.

In the following description where symbols appearing in formulae are notspecifically defined, it is to be understood that they are “ashereinbefore defined” in accordance with the first definition of eachsymbol in the specification.

It is to be understood that in the descriptions of the followingprocesses the sequences may be performed in different orders, and thatsuitable protecting groups may be required to achieve the compoundssought.

According to a feature of the present invention compounds of formula (I)in which R represents hydrogen may be prepared by the reaction of acompound of formula (II):

wherein L is a leaving group and R¹, R², R³, n and X are as hereinbeforedefined with hydroxylamine or a salt of hydroxylamine. Hydroxylaminehydrochloride is generally preferred. Generally L is alkoxy, for exampleethoxy, or N,N-dialkylamino, for example dimethylamino. The reaction isgenerally carried out in an organic solvent such as ethanol oracetonitrile or a mixture of a water-miscible organic solvent and water,preferably in a ratio of organic solvent: water of from 1:99 to 99:1,optionally in the presence of a base or acid acceptor such astriethylamine or sodium acetate at a temperature from room temperatureto the boiling point of the solvent. The intermediates of formula (II)are novel and as such constitute a further feature of the presentinvention.

According to a further feature of the present invention compounds offormula (I) in which R represents hydrogen may be prepared by thereaction of a compound of formula (III):

wherein R¹ is as hereinbefore defined and Y′ represents a carboxy groupor a reactive derivative thereof (such as a carboxylic acid chloride orcarboxylic ester), or a cyano group, with an appropriate organometalicreagent such as a Grignard reagent or an organolithium reagent. Thereaction is generally carried out in an inert solvent such as ether ortetrahydrofuran at a temperature from 0° C. to the reflux temperature ofthe mixture.

According to a further feature of the present invention compounds offormula (I) wherein R represents a group —CO₂R⁴ may be prepared by thereaction of a compound of formula (IV)

wherein R¹, R²; R³, X and n are as hereinbefore defined and P is aleaving group such as N,N-dialkylamino, with a compound of formulaR⁴O₂CC(Z′)═NOH wherein R⁴ is as hereinbefore defined and Z′ is a halogenatom. Generally Z′ is chlorine or bromine. The reaction is generallyperformed in an inert solvent such as toluene or dichloromethane eitherin the presence of a base such as triethylamine or a catalyst such as a4 Angstrom molecular sieve or fluoride ion.

According to a further feature of the present invention compounds offormula I in which R represents a group —CO₂R⁴ may be prepared by thereaction of a compound of formula (V):

wherein R¹, R², R³, X and n are as hereinbefore defined with a compoundof formula R⁴O₂CC(Z′)═NOH wherein Z′ and R⁴ are as hereinbefore defined.The reaction is generally performed in an inert solvent such as tolueneor dichloromethane optionally in the presence of a base such astriethylamine or a catalyst such as a 4 Angstrom molecular sieve orfluoride ion. The reaction can be carried out at a temperature betweenroom temperature and the reflux temperature of the mixture.

According to a further feature of the present invention compounds offormula (I) wherein R represents —CO₂R⁴ may be prepared by the reactionof a salt of compounds of formula (VI):

wherein R¹, R², R³, X and n are as hereinbefore defined with a compoundof formula R⁴O₂CC(Z′)═NOH wherein R⁴ and Z′ are as hereinbefore defined.Preferred salts include sodium or magnesium salts. The reaction may beperformed in an inert solvent such as dichloromethane or acetonitrile ata temperature between room temperature and the reflux temperature of themixture. The salt of a compound of formula (VI) is generally prepared insitu by treating the compound of formula (VI) with a base. Examples ofsuitable bases include alkaline earth metal alkoxides such as magnesiummethoxide.

According to a further feature of the present invention compounds offormula (I) in which X represents —NH— may be prepared by thedeprotection of a compound of formula (VII):

wherein R, R¹, R² and n are as hereinbefore defined and A represents—NX¹R³ wherein R³ is as hereinbefore defined and X¹ represents aprotecting group which can be removed under acidic or neutral reactionconditions. The protecting group may be for example a benzyl group(which may be removed by hydrogenolysis) or a t-butyloxycarbonyl group(t-BOC). Suitable methods of protection and deprotection are describedin the literature (for example in “Protective Groups in OrganicSynthesis”, by T. W. Greene and P. G. M. Wuts). The intermediates offormula (VII) are novel and as such constitute a further feature of thepresent invention.

According to a further feature of the present invention compounds offormula (I) in which R³ represents a group —C(Z)═Y and Z is selectedfrom R⁶³, —NR⁶⁰R⁶¹ (wherein R⁶⁰ and R⁶¹ are not hydrogen), —SR⁶³ or—OR⁶³ may be prepared by the reaction of a compound of formula (VIII):

with a compound of formula A¹—CZ(═Y), wherein A¹ is a leaving group andZ is as defined above. Preferably A¹ is chlorine. The reaction isgenerally performed in the presence of a weak base, e.g. caesiumcarbonate and in an inert solvent (e.g. acetonitrile) at a temperaturefrom room temperature to reflux.

According to a further feature of the present invention compounds offormula (I) in which R³ represents a group —C(Z)═Y and Z is —NHR⁶⁰ maybe prepared by the reaction of the corresponding compound of formula(VII) with a compound of formula R⁶⁰—N═C═Y, wherein R⁶⁰ is ashereinbefore defined. The reaction is generally performed in an inertsolvent at a temperature from room temperature to reflux.

Intermediates in the preparation of compounds of formula (I) may beprepared by the application or adaptation of known methods.

Compounds of formula (II) may be prepared by the reaction of compoundsof formula (VI) with either a trialkyl orthoformate such as triethylorthoformate or a dimethylformamide dialkyl acetal such asdimethylformamide dimethyl acetal

The reaction with a trialkyl orthoformate can be carried out in thepresence of acetic anhydride at the reflux temperature of the mixtureand the reaction with dialkylformamide dialkyl acetal is carried outoptionally in the presence of an inert solvent at a temperature fromroom temperature to the reflux temperature of the mixture.

Compounds of formula (IV) may be prepared by the reaction of a compoundof formula R¹C(P)═CH₂ with a benzoyl chloride of formula (IX):

The reaction is generally carried out in the presence of an organic basesuch as triethylamine in an inert solvent such as toluene ordichloromethane at a temperature between −20° C. and room temperature.

Compounds of formula (V) may be prepared by the metallation of theappropriate acetylene of formula (X):

R¹C≡CH  (X)

followed by reaction of the metal salt thus obtained with a benzoylchloride of formula (IX). The metallation is generally performed usingn-butyl lithium in an inert solvent such as ether or tetrahydrofuran ata temperature from −78° C. to 0° C. The subsequent reaction with thebenzoyl chloride is carried out between −78° C. and room temperature.

Compounds of formula (VI) may be prepared by the reaction of an acidchloride of formula (IX) with the metal salt of a compound of formula(XI):

R¹COCH₂CO₂tBu  (XI)

wherein R¹ is as hereinbefore defined, to give a compound of formula(XI):

wherein R¹, R² R³, X and a are as hereinbefore defined, which issubsequently decarboxylated to give a compound of formula (VI).Generally the reaction to produce the compound of formula (XII) isperformed in a solvent such as a lower alcohol, preferably methanol, inthe presence of a metal preferably magnesium. The reaction may also beperformed using a pre-prepared metal salt of a compound of formula (XI).The decarboxylation is generally performed by refluxing the compound offormula (XII) in the presence of a catalyst, such asparatoluenesulphonic acid or trifluoroacetic acid, in an inert solvente.g. toluene or 1,2-dichloroethane.

Compounds of formula (VI) may also be prepared by the reaction of abenzoic acid ester of formula (XV):

wherein R², R³, X and n are as hereinbefore defined and R¹² represents alower alkyl group, with a compound of formula (XIV):

R¹C(O)CH₃  (XIV)

wherein R¹ is as hereinbefore defined. The reaction is generallyperformed in a solvent such as ether, tetrahydrofuran orN,N-dimethylformamide, in the presence of a base, preferably an alkalimetal base such as sodium hydride, at a temperature from 0° C. to thereflux temperature.

Compounds of formula (VI) in which —XR³ represents —NHCONR⁶⁰R⁶¹ may alsobe prepared by the reaction of a compound of formula (XV):

with a ketone of formula (XIV) above in the presence of a base,preferably lithium diisopropylamide in an inert solvent at a temperaturefrom 78° C. to room temperature.

Compounds of formula (VII) may be prepared by the processes hereinbeforedescribed for preparing compounds of formula (I) in which R, R¹, R² andn are as hereinbefore defined and the group —XR³ is replaced by thegroup A.

Compounds of formula (VIII) may be prepared by the hydrolysis of thecorresponding compound of formula (I) in which R³ is replaced by aprotecting group, for example alkylsulphonyl (preferablymethylsulphonyl). The hydrolysis is generally performed using an acid,preferably sulphuric acid, in an inert solvent (e.g. acetic acid) at atemperature from room temperature to reflux. Compounds of formula (I) inwhich R³ is replaced by a protecting group may be prepared by theprocesses hereinbefore described for preparing compounds of formula (I)in which R, R¹, R² and n are as hereinbefore defined and the group R³ isreplaced by a protecting group.

Acid chlorides of formula (IX) may be prepared by the reaction of abenzoic acid of formula (XVI):

with a chlorinating agent, for example thionyl chloride at the refluxtemperature of the mixture. In some cases the benzoyl chlorides may alsobe prepared by reaction of the benzoic acid with oxalyl chloride in asolvent such as 1,2-dichloroethane at from ambient to refluxtemperature.

A number of the benzoic acids of formula (XVI) are novel and as suchconstitute a flirter feature of the present invention. Compounds offormula (XVI) in which R² represents a halogen atom or a group selectedfrom trifluoromethyl, methyl, C₁₋₂ haloalkoxy and S(O)_(p)Me wherein pis zero, one or two; X represents —NR⁸′ wherein R⁸ represents alkyl oralkenyl containing up to four carbon atoms optionally substituted by oneor more halogen atoms; n represents one or two; R³ represents —C(Z)═Ywherein Y is oxygen, Z is R⁶³ or —OR⁶³ and R⁶³ represents alkylcontaining up to four carbon atoms optionally substituted by one or morehalogen atoms, are especially preferred.

Compounds of formula (XV) may be prepared by the application oradaptation of known methods, for example as described in Acta. Chim.Acad. Sci. 107(1), 57 (1981).

Compounds of formula (XVI) in which the group —XR³ is ortho to the acidgroup and R³ is —C(O)R⁶³ may be prepared by the reaction of a compoundof formula (XVII):

wherein X² is chlorine or preferably bromine or iodine, with a compoundof formula R⁸′NHC(O)R⁶³ in the presence of a strong base. Generally thereaction is performed in the presence of a catalyst e.g. copper (I)chloride or preferably copper (I) bromide or iodide, in an inert solventsuch as dioxan or toluene. The preferred strong base is sodium hydrideand the reaction is conveniently performed at a temperature from 50° C.to reflux

Intermediates of formula (VI) in which the group —XR³ is ortho to thecarbonyl group and represents a group R⁸′NC(O)R⁶³ may be prepared by thereaction of a compound of formula (XVIII):

wherein X² is chlorine or preferably bromine or iodine, with a compoundof formula R⁸′NHC(O)R⁶³ in the presence of a strong base. Generally thereaction is performed in the presence of a catalyst e.g. copper (I)chloride or preferably copper (I) bromide or iodide, in an inert solventsuch as dioxan or toluene. The preferred strong base is sodium hydrideand the reaction is conveniently performed at a temperature from 50° C.to reflux.

Intermediates of formula (XVI) in which R³ represents —CO₂R⁶³ may beprepared by the reaction of the corresponding compound of formula (XVI)in which R³ represents hydrogen with a compound of formula Cl—CO₂R⁶³ inthe presence of a base. The base may be pyridine or triethylamine orpreferably an alkali metal carbonate e.g. sodium carbonate and thereaction is performed in an inert solvent (e.g. water) at a temperaturefrom 0° C. to 100° C., for example according to the method described inOrg. Synthesis Coll. Vol. 3, 167.

Intermediates of formula (M), (X), (XI), (XIII), (XIV), (XVII) and (XVM)are known or may be prepared by the application or adaptation of knownmethods.

Agriculturally acceptable salts of compounds of formula (I) may beprepared by the application or adaptation of known methods.

Those skilled in the art will appreciate that some compounds of formula(I) may be prepared by the interconversion of other compounds of formula(I) and such interconversions constitute yet more features of thepresent invention. Examples of such interconversions are hereafterdescribed.

According to a further feature of the present invention compounds inwhich p and/or q is one or two may be prepared by the oxidation of thesulphur atom(s) of the corresponding compounds in which p and/or q is 0or 1. The oxidation of the sulphur atom(s) is generally carried outusing for example 3-chloroperoxybenzoic acid in an inert solvent such asdichloromethane at a temperature from −40° C. to room temperature.

The following examples illustrate the preparation of compounds offormula (I) and the following reference examples illustrate thepreparation of intermediates of the invention. In the presentspecification b.p. means boiling point; m.p. means melting point; cPrrepresents cyclopropyl. Where the letters NMR appear, thecharacteristics of the proton nuclear magnetic resonance spectrum follow(in ppm, solvent CDCl₃ unless otherwise stated).

EXAMPLE 1

Hydroxylamine hydrochloride (0.1 g) was added to a stirred solution of1-[4-chloro-2-(N-methylacetamido)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-one(0.32 g) in ethanol. The mixture was stirred for 0.75 hours andevaporated to dryness. Water was added to the residue, which wasextracted (dichloromethane). The extract was dried (magnesium sulphate)and evaporated to give an oil. This was purified by chromatographyeluting with ethyl acetate/dichloromethane (1:8) to give4-[4-chloro-2-(N-methylacetamido)benzoyl]-5-cyclopropylisoxazole,(compound number 1, 0.12 g), m.p. 106.5-107.5° C., as a white solid.

EXAMPLE 2

Hydroxylamine hydrochloride (0.53 g) and sodium acetate (0.63 g) wereadded to a stirred solution of1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione(2.88 g) in ethanol. After 05 hours water was added, and the mixtureextracted (dichloromethane), dried (magnesium sulphate) and evaporatedto dryness. Purification by chromatography gave4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 2, 1.09 g), m.p. 76-78° C. as a white solid.

By proceeding in a similar manner the following compounds of theinvention were prepared from the appropriately substituted startingmaterials:

4-[3,4-chloro-2-(N-methyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole,(compound number 3), m.p. 124.5-127.5° C.

4-[3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 4). m.p. 129-131° C.

4-[3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 5), NMR 0.95(d,3H), 1.1(d,3H), 1.3(m,2H), 1.4(m,2H),2.8(m,1H), 3.2(s,3H), 4.85(m,1H), 7.3(d,1H), 7.55(d,1H), 8.1(s,1H).

4-[4-bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 6), NMR 1.3(m,10H), 2.75(m,1H), 3.45(s, 3H), 3.7(m,3H),4.0(m,2H), 7.05(d,1H), 7.6(d,1H), 8.15(s,1H).

4-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)benzoyl]-5-cyclopropylisoxazole(compound number 7), NMR 1.2(m,10H), 2.7(m,1H), 3(s,3H), 3.65(m,2H),4.2(m,1H), 4.5(m,1H), 7.1(d,1H),7.6(d,1H), 8.1(s,1H).

4-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxybenzoyl]-5-cyclopropylisoxazole(compound number 8), NMR 1.2(m,6H), 1.4(s,3H), 3.5(s,2H), 3.65(m,3H),3.85(s,3H), 7.1(d,1H), 7.6(d,1H), 8.0(s,1H).

4-[3,4-dichloro-2-N-propyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 9), NMR 0.85(t,3H), 1.6(m,2H), 2.75(m,1H), 3.35(m,2H),3.6(s,3H), 7.25(d,1H), 7.55(d,1H), 8.05(s,1H).

4-[3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 10), NMR 1.1(d,3H), 1.2(d,3H), 1.3(m,4H), 2.8(m,1H),3.6(s,3H), 4.3(m,1H), 7.25(d,1H), 7.55(d,1H), 8.1(s,1H).

4-[3,4-dichloro-2-(N-alkyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 11), NMR 1.25(m,2H), 1.35(m,2H), 2.7(m,1H), 3.6(s,3H),4.15(m2), 5.0(m,2H), 5.9(m,1H), 7.25(d,1H), 7.55(d,1H), 8.05(s,1H).

4-[3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 12), m.p. 98° C.

4-[3,4-dichloro-2-(N-ethyl-N-propyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole,(compound number 13), m.p. 81-81.5° C.

4-[3,4-dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 14), m.p. 78° C.

4-[3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino]-5-cyclopropylisoxazole(compound number 15), NMR 0.85(t,3H), 1.1-1.6(m,11H), 2.8(m,1H),3.47(m,1H), 3.7(m,1H), 3.9(m,1H), 4.1(m,1H), 7.3(d,1H), 7.56(d,1H),8.07(s,1H).

4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-isopropylisoxazole(compound number 16), m.p. 90-91° C.

EXAMPLE 3

A mixture of4-[4-bromo-3-ethoxy-2-(methylamino,benzoyl]-5-cyclopropylisoxazole(0.096 g), methyl chloroformate (0.08 ml) and caesium carbonate (0.04 g)in acetonitrile was heated under reflux for 3 hours. Dichloromethane andwater were added to the cooled mixture, the organic phase separated,dried (anhydrous magnesium sulphate) and evaporated in vacuo to give,after purification,4-[4-bromo-3-ethoxy-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 17, 0.07 g) as a yellow gum, NMR 1.25(m,2H),1.35(m,2H), 1.46(t,3H), 2.7(m,1H), 3.25(s,3H), 3.45(s,3H), 4.0(m,2H),7.1(d,1H), 7.6(d,1H), 8.2(s, 1H).

By proceeding in a similar manner the following compounds of theinvention were prepared from the appropriately substituted startingmaterials:

4-[4-chloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 18), NMR 1.2(m,2H), 1.3(m,2H), 2.7(m,1H), 3.2(s,3H),3.5(brs,3H), 7.4(m,3H), 8.2(s,1H).

5-cyclopropyl-4-[3,4-difluoro-2-N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole(compound number 19) as a white solid, m.p. 118-1195° C.

4-[4-chloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 20), NMR 1.2(m,7H), 2.7(m,1H), 3.6(m,4H), 7.3(s,1H),7.4(s,2H), 8.2(s,1H).

4-[4-chloro-2-(N-propyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 21) as a brown oil, NMR 0.8(t,3H), 1.2(m,2H),1.3(m,2H), 1.6(q,2H), 2.6(m,1H), 3.5(m,5H), 7.2(s,1H), 7.3(s,2H),8.1(s,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-fluorobenzoyl]isoxazole(compound number 22), NMR 1.2(m,7H), 1.6(m,1H), 3.5(m,4H), 6.95(m,2H),7.4(t,1H), 8.1(s,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole(compound number 23), m.p. 81.7-83.7° C.

5-cyclopropyl-4-[2-(N-ethyl-N-ethoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole(compound number 24), m.p. 89-91.5° C.

5-cyclopropyl-4-[2-(N-ethyl-N-isopropyloxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole(compound number 25), m.p. 74-76° C.

5-cyclopropyl-4-[2-(N-methyl-N-methoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole(compound number 26), NMR 1.2(brs,2H), 1.3(brs,2H), 2.6(brs,1H),3.2(s,3H), 3.5(brd,3H), 7.5(m,3H), 8.1(brd,1H).

4-[4-bromo-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 27), NMR 12(brs,2H), 1.3(brs,2H), 2.6(m,1H), 3.2(s,3H),3.5(brd,3H), 7.3(d,1H), 7.5(m,2H), 8.1(brd,1H).

5-cyclopropyl-4-[4-iodo-2-(N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole(compound number 28), NMR 1.2(brs,2H), 1.3(brs,2H), 2.6(m,1H),3.2(s,3H), 35(brd,3H), 7.1(d,1H), 7.6(m,2H), 8.1(brd,1H).

5-cyclopropyl-4-[2-(N-methyl-N-methoxycarbonylamino)-4-trifluoromethoxybenzoyl]isoxazole(compound number 29), NMR 1.1(brs,2H), 1.2(brs,2H), 2.6(brs,1H),3.2(s,3H), 3.5(brd,3H), 7.1(r,7.4(d,1H), 8.1(brd,1H).

4-[4-chloro-2-(N-isobutyl-N-methoxycarbonylamino)benzoyl]-5cyclopropylisoxazole(compound number 30), NMR 0.8(d,6H), 1.2(brs,2H), 1.3(brs,2H),1.8(m,1H), 2.6(m,1H), 3.5(m,5H), 7.3(m,3H), 8.1(brs,1H).

4-[3,4-dichloro-2-(N-methyl-N-methylthiocarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 31) as a white solid, m.p. 175-177° C.

5-cyclopropyl-4-[4-methyl-2-N-methyl-N-methoxycarbonylamino)benzoyl]isoxazole(compound number 32), NMR 1.2(brs,2H), 1.3(brs,2H), 2.4(s,3H),2.6(m,1H), 3.2(s,3H), 3.5(brd,3H), 7.1(m,2H), 7.3(d,1H), 8.1(brd,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-4-methylsulphonylbenzoyl]isoxazole(compound number 33), NMR 1.2(m,5H), 1.3(m,2H), 2.6(m,1H), 3.1(s,3H),3.6(brd,5H), 7.6(d,1H). 7.9(m,2H), 8.1(brs,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino]isoxazole (compoundnumber 34), m.p. 60.5-61.5° C.

4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-(methylthio)benzoyl]-5-cyclopropylisoxazole(compound number 35), m.p. 126.5-129° C.

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3,4-difluorobenzoyl]isoxazole(compound number 36), NMR 1.15(m,2H), 1.25(t,3H), 1.35(m,2H), 2.7(m,1H),3.4(q,2H), 3.55(s,3H), 7.2(m,2H), 8.1(s,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-(methylthio)benzoyl]isoxazole(compound number 37), NMR 1.15(m,2H), 1.25(m,3H), 1.35(m,2H),2.55(s,3H), 2.7(m,1H), 3.4(q,2H), 3.55(s,3H), 7.2(m,2H), 8.15(s,1H).

4-[chloro-2-(N-ethyl-N-methoxycarbonylamino)-3-fluorobenzoyl]-5-cyclopropylisoxazole(compound number 38), m.p. 103-105° C.

4-[3,4-dibromo-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 39), NMR 1.15(t,3H), 1.3(m,4H), 2.7(m,1H), 3.6(m,2H),3.62(s,3H), 5.3(s,1H), 7.25(d,1H), 7.7(d,1H), 8.1(s,1H).

4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 40), m.p. 88-89° C.

5-cyclopropyl-4-[2-(N-ethyl-N-phenoxycarbonylamino)-4-trifluoromethylbenzoyl]isoxazole(compound number 41), NMR 1.3(m,7H), 2.7(m,1H), 3.8(brd,2H), 6.9(m,1H),7.2(m,4H), 7.7(m,3H), 8.1(brd,1H).

4-[4-chloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 42), NMR 1.15(m,8H), 1.27(m,2H), 2.64(m,1H),3.6(brs,2H), 3.97(q,2H), 7.3(m,3H), 8.14(s,1H).

4-[4-chloro-2-(N-propyl-N-propyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 43), NMR 0.75(t,3H), 0.82(t,3H), 1.12(m,2H),1.25(m,2H), 1.46(m,2H), 157(m,2H), 2.62(m,1H), 3.45(brs,2H), 3.88(t,2H),72(m,3H), 8.08(s,1H).

4-[4-chloro-2-(N-propyl-N-ethoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 44), NMR 0.91(t,3H), 1.12(t,3H), 1.22(m,2H),1.34(m,2H), 1.65(m,2H), 2.68(m,1H), 3.54(brs,2H), 4.05(q,2H), 7.3(m,3H),8.17(s,1H).

4-[4-chloro-2-(N-propyl-N-n-butyloxycarbonylamino)benzoyl]-5-cyclopropylisoxazole(compound number 45), NMR 1.0(m,6H), 1.31(m,2H), 1.38(m,2H), 1.45(m,2H),1.6(m,2H), 1.75(m,2H), 2.8(m,1H), 3.62(brs,2H), 4.11(t,2H), 7.4(m,3H),8.29(s,1H).

EXAMPLE 4

Magnesium turning (0.1 g) were heated under reflux in methanol untildissolved, and a solution of1-[3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropan-1,3-dione(1.3 g) in methanol was added at room temperature. Heating under refluxwas resumed for 1 hour, the solvent evaporated and the residue wasdissolved in dichloromethane. A solution of ethyl chloroximidoacetate(0.68 g) in dichloromethane was added and the mixture stirred overnight.Hydrochloric acid solution (2M) was added, and the organic layer wasextracted, washed (water), dried (anhydrous magnesium sulphate) and thesolvent evaporated to give, after recrystailisation from ethanol, ethyl4-[3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole-3-carboxylate(compound 46, 0.54 g) as white crystals, m.p. 119-122° C.

By proceeding in a similar manner ethyl4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole-3-carboxylate(compound 47) was prepared from the appropriately substituted startingmaterials, NMR 1.1(t,3H), 1.25(m,7H), 2.35(m,1H), 33-3.85(m,2H),3.6(s,3H), 4.2(m,2H), 7.4(d,1H), 7.52(d,1H).

EXAMPLE 5

m-Chloroperbenzoic acid (1.81 g of a 50% oil dispersion) was added to astirred solution of4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-(methylthio)benzoyl]-5-cyclopropyl-isoxazole(compound 35, 0.92 g) in dichloromethane. After 5 hours, a solution ofsodium metabisulphite was added and the mixture stirred for 5 minutes.The organic phase was washed with sodium bicarbonate solution and water,dried (anhydrous magnesium sulphate) and evaporated. The residue wastriturated (with a hexane/ether solution) to yield4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole(compound number 48, 0.95 g) as a white solid, m.p. 152-155.5° C.

By proceeding in a similar manner the following compounds of theinvention were prepared:

5-cyclopropyl-4-[2-N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-methylsulphonylbenzoyl]isoxazole(compound number 49), m.p. 127.5-131° C. (from compound 37).

5-cyclopropyl-4-[2-(N-ethyl-N-methoxycarbonylamino)-3-fluoro-4-methylsulphinylbenzoyl]isoxazole(compound number 50), m.p. 43-48° C. (also from compound 37).

Reference Example 1

A mixture of1-[4-chloro-2-(N-methylacetamido)phenyl]-3-cyclopropane-1,3-dione (0.3g) and N,N-diethylformamide dimethyl acetal (0.3 ml) was heated in drytoluene at 65° C. for 3 hours. The solution was evaporated to drynessand re-evaporated after addition of toluene to give1-[4-chloro-2-(N-methyl-acetamido)phenyl]-3-cyclopropyl-2-dimethylamino-methylenepropane-1,3-dione(0.32 g) as a brown oil, which was used directly in the next stage.

By proceeding in a similar manner employing dichloromethane as solventat reflux for 3 days the following compounds were also prepared from theappropriately substituted starting materials:

1-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)-phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione;

1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione;

3-cyclopropyl-2-dimethylaminomethylene-1-[4-methyl-2-(N-methyl-N-methylsulphonylamino)phenyl]propane-1,3-dione;

1-[4-chloro-2-(N-propyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione;

3-cyclopropyl-2-dimethylaminomethylene-1-dione;

3-cyclopropyl-2-dimethylaminomethylene-1-[2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylphenyl]-propane-1,3-dione;

1-[3,4-dichloro-2-(N-methyl-N-methylsulphonylamino)-phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione;

1-[4-bromo-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione;

3-cyclopropyl-2-dimethylaminomethylene-1-[3,4-difluoro-2-(N-methyl-N-methylsulphonylamino)phenyl]-propane-1,3-dione;

3-cyclopropyl-2-dimethylaminomethylene-1-[4-iodo-2-(N-methyl-N-methylsulphonylamino)phenyl]-propane-1,3-dione;and

1-[2-(N-isobutyl-N-methylsulphonylamino)-4-chlorophenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione.

Reference Example 2

N-methyl-acetamide (0.24 g) was added to a suspension of sodium hydride(0.4 g, 60% oil dispersion) in dry dioxan (30 ml). To this was added1-(2-bromo-4-chlorophenyl)-3-cyclopropylpropane-1,3-dione (1.0 g)followed by copper (I) bromide (1.0 g) and the mixture heated at refluxfor 7 hours and allowed to stand at ambient temperature for 3 days.After evaporation to dryness the residue was added to dilutehydrochloric acid and extracted (ethyl acetate). The extract was washed(water), dried (magnesium sulphate) and evaporated to dryness.Purification by chromatography gave1-[4-chloro-2-(N-methylacetamido)phenyl]-3-cyclopropane-1,3-dione (0.32g) as an orange solid, m.p. 110-112° C.

Reference Example 3

Cyclopropylmethylketone (4.0 g) was added to a suspension of sodiumhydride (3.2 g, 60% oil dispersion) in dry tetrahydrofuran (10 ml). Whenthe evolution of hydrogen had subsided, a solution of methyl2-bromo-4-chlorobenzoate (10.0 g) in tetrahydrofuran was added dropwise.The resulting mixture was heated at reflux overnight, cooled, evaporatedto dryness and poured onto dilute hydrochloric acid. The mixture wasextracted (dichloromethane), dried (magnesium sulphate) and evaporatedto give, after purification by chromatography,1-(2-bromo-4-chlorophenyl)-3-cyclopropyl-propan-1,3-dione (3.07 g), m.p.42-45° C. as an orange solid.

Reference Example 4

A solution of1-[3,4-dichloro-2-(N-methyl-methoxycarbonylamino)phenyl]-3-cyclopropane-1,3-dione(2.81 g) and triethylorthoformate (2.42 g) in acetic anhydride (25 g)was heated at reflux for 1.5 hours, cooled and evaporated to dryness togive1-[3,4-dichloro-2-(N-methyl-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione(3.58 g) which was used directly in the next stage.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted stating materials:

1-[3,4-dichloro-2-(N-methyl-ethoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione,isolated as a brown oil.

1-[3,4-dichloro-2-(N-ethyl-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3dione.

1-[4-bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3dione.

1-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxyphenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-propyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-alkyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-ethyl-N-propyloxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-2-ethoxymethylene-3-isopropylpropane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-ethyl-N-methylsulphonylamino)phenyl]propane-1,3-dione.

1-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-ethyl-N-methylsulphonylamino)-3,4-difluorophenyl]propane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-ethyl-N-methylsulphonylamino)-3-fluoro-4-(methylthio)phenyl]propane-1,3-dione.

1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)-3-fluorophenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[3,4-dibromo-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-ethyl-N-methylsulphonylamino)-4-fluorophenyl]propane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-ethyl-N-methylsulphonylamino)-4-trifluoromethylphenyl]propane-1,3-dione.

1-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

1-[4-chloro-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione.

3-cyclopropyl-2-ethoxymethylene-1-[2-(N-propyl-N-methylsulphonylamino)-4-trifluoromethoxyphenyl]propane-1,3-dione.

Reference Example 5

A suspension of 3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoylchloride (3.5 g) in dry toluene was added dropwise during 0.25 hours toa stirred solution of tert-butyl 3-cyclopropyl-3-oxopropionate magnesiumenolate (3.5 g) in toluene at room temperature. Stirring was maintainedovernight and hydrochloric acid (2M) added. The toluene layer wasseparated and dried by azeotropic distillation before addition ofpara-toluenesulphonic acid (0.1 g). The mixture was heated at reflux for4 hours, allowed to cool, washed (water) and evaporated to dryness. Theresidue was purified by chromatography to give1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione(2.49 g), NMR 1.0(m,2H), 1.1-1.3(2t,3H), 1.2(m,2H), 1.7(m,1H),3.4-3.7(2m,2H), 3.6-3.8(2s, 5.9(s,1H), 7.5(m,2H), 16.0(s,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

1-[3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dioneas a brown oil, NMR 0.9(m,2H), 1.0.-1.3(2t,3H),1.1(m,2H), 3.1(s,3H),4.1-4.2(2m,2H), 5.9(s,1H), 7.5(m,2H), 16.0(s,1H).

1-[3,4-chloro-2-(N-methyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dioneas a brown gum, NMR 0.9(m,2H), 1.1(m,2H), 1.6(m,1H), 3.0(s,3H), 3.5 and3.7(2s,3H), 5.8(s,1H), 7.4(m,2H), 16.0(s,1H).

1-[3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.1(m,6H), 1.2(m,2H), 1.7(m,1H), 3.1(s,1H), 4.95(m,1H),5.9(s,1H), 7.5(s,2H), 15.95(s,1H).

3-cyclopropyl-1-[2-(N-ethyl-N-methylsulphonylamino)-4-fluorophenyl]propane-1,3-dione,NMR 1.0(m,2H), 1.15(t,3H), 1.2(m,2H), 1.8(m,1H), 3.0(s,3H), 3.55(m,6H),6.1(s,1H), 7.2(m,2H), 7.6(t,1H), 16.2(s,1H).

1-[4-bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.15(m,5H), 1.4(m,3H), 1.7(m,1H), 3.6(s,3H), 3.75(q,2H),4.0(m,2H), 5.9(s,1H), 7.25(d,1H), 7.55(d,1H).

1-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.1(m,8H), 1.7(m,1H), 3.6(s,3H), 3.65(m,2H), 4.2(m,1H), 4.5(m,1H),5.85(s,1H), 7.35(d,1H), 7.6(d,1H), 16.0(s,1H).

1-[4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxyphenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.1(m,7H), 1.7(m,1H), 3.6(m,4H), 3.85(t,4H), 5.85(s,1H), 7.25(d,1H),7.6(d1H).

3-cyclopropyl-1-[2-(N-ethyl-N-methylsulphonylamino)phenyl]propane-1,3-dione,NMR 1.0(m,2H), 1.2(m,2H), 1.25(t,3H), 1.75(m,1H), 3.0(s,3H), 3.65(m,2H),6.1(s,1H), 7.4(m,2H), 7.5(m,1H), 7.6(m,1H), 16.1(brs,1H).

1-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)phenyl]-3-cyclopropylpropane-1,3-dione,m.p. 101-102° C.

3-cyclopropyl-1-[2-(N-ethyl-N-methylsulphonylamino)-3,4-difluorophenyl]propane-1,3-dione,NMR 1.05(m,2H), 1.15(t,3H), 1.2(m,2H), 1.8(m,1H), 3.1(s,3H), 3.6(q,2H),6.75(s,1H), 7.25(m,1H), 7.45(m,1H), 16.1(brs,1H).

3-cyclopropyl-1-[2-(N-ethyl-N-methylsulphonylamino)-3-fluoro-4-(methylthio)phenyl]propane-1,3-dione,NMR 1.0(m,2H), 1.2(m,2H), 1.25(t,3H), 1.8(m,1H), 2.5(s,3H), 3.1(s,3H),3.6(q,2H), 6.3(s, 1H), 7.25(m,1H), 7.5(m,1H), 16.15(brs, 1H).

1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)-3-fluorophenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.15(t,3H), 1.2(m,2H), 3.1(s,3H), 3.6(q,2H), 6.25(s,1H),7.5(m,2H), 16.0(brs,1H).

1-[3,4-dibromo-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.2(m,7H), 1.75(m,1H), 3.05(s,3H), 3.75(m,2H), 6.0(s,1H), 7.3(d,1H),7.7(d,1H).

1-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.15(m,5H), 1.7(m,1H), 3.0(s,3H), 3.65(m,2H), 6.0(s,1H),7.3(t,1H), 7.4(d,1H), 7.5(d,1H), 15.9(brs,1H).

1-[3,4-dichloro-2-(N-propyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 0.85(t,3H), 1.0(t,2H), 1.2(t,2H), 1.55(m,2H), 1.7(m,1H), 3.25(m,2H),3.7(s,3H), 5.85(s,1H), 7.5(m,2H), 15.9(brd,1H).

1-[3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.1(m,10H), 1.7(m,1H), 3.7(s,3H), 4.25(m,1H), 5.85(s,1H),7.45(m,2H), 15.8(brd,1H).

1-[4-dichloro-2-(N-allyl-N-methoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.2(m,2H), 1.75(m,1H), 2.35(s,2H), 3.7(s,3H), 4.05(m,1H),5.0(t,2H), 5.85(s,2H), 7.25(m,1H), 7.45(m,1H), 15.9(brd,1H).

1-[3,4-chloro-2-(N-ethyl-N-propyloxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0(m,2H), 1.2(m,2H), 1.3(t,3H), 1.7(m,1H), 4.2(q,2H), 6.07(s,1H),7.4(d,1H), 7.46(d,1H), 16.05(brs,1H).

1-[3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 1.0-1.2(m,10H), 1.7(m,1H), 3.45(m,1H), 3.73(m,1H), 4.2(m,2H),5.88(s,1H), 7.5(s,2H), 15.9(brs, 1H).

1-[3,4 -dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione, NMR 1.0-1.2(m,8H), 1.35(m,2H),1.59(m,1H), 3.42(m,1H), 3.7(m,1H), 5.03(m,1H), 5.88(s,1H), 75(s,2H),15.88(brs,1H).

1-[3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 0.84(t,3H), 1.0-1.26(m,9H), 1.5(m,2H), 1.7(m,1H), 3.42(m,1H),3.73(m,1H), 4.11(t,2H), 5.88(s,1H), 7.5(s,2H), 15.95(brs,1H).

1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-isopropylpropane-1,3-dione,NMR 1.08(t,3H), 1.2(d,6H), 2.58(m,1H), 3.47(m,1H), 3.7(m,1H), 3.7(s,3H),5.8(s,1H), 7.5(s,2H), 15.6(brs,1H).

1-[4-chloro-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,93.3-96.5° C.

1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 0.9-1.4(m,7H), 1.07-1.9(m,1H), 3.0(s,3H), 3.65(q,2H), 6.1(s,1H),7.4(m,2H), 7.55(d,1H), 16.0-16.3(brs,1H).

3-cyclopropyl-1-[4-methyl-2-(N-methyl-N-methylsulphonylamino)phenyl]propane-1,3-dione,NMR 0.9-1.1(m,2H), 1.15-1.25(m,2H), 1.7-1.85(m,1H), 2.35(s,3H),2.95(s,3H), 3.25(s,3H), 6.1(s,1H), 7.15(d,1H), 7.2(s,1H), 7.5(d,1H),16.1-16.3(brs,1H).

1-[4-2-chloro-2-(N-propyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 0.9(t,3H), 1.05(m,2H), 1.25(m,2H), 1.45-1.65(m,4H), 1.78(m,1H),3.03(s,3H), 6.15(s,1H), 7.38-7.48(m,2H), 7.57(dd,1H), 16.12(brs,1H).

3-cyclopropyl-1-[2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylphenyl]propane-1,3-dione,NMR 1.0-1.3(m,7H), 1.79(m,1H), 3.0(s,3H), 6.15(s,1H), 7.78(d,1H),7.98(m,2H).

1-[3,4-chloro-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione.

3-cyclopropyl-1-[2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethylphenyl]propane-1,3-dione.

3-cyclopropyl-1-[2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethoxyphenyl]propane-1,3-dione,NMR 1.0(m,2H), 1.2(m,1H), 1.7(m,1H), 3.0(s,3H), 3.25(s,3H), 6.05(s,1H),7.25(m,2H), 7.6(d,1H), 16.0(s,1H).

3-cyclopropyl-1-[4-iodo-2-(N-methyl-N-methylsulphonylamino)phenyl]propane-1,3-dione,m.p. 131.5-134.° C.

Reference Example 6

Sodium hydroxide solution (2M, 44.6ml) was added dropwise during 5minutes to a stirred solution of methyl3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoate (9.1 g) inmethanol. After 0.5 hours the methanol was evaporated, the residuediluted (water), washed (ether), acidified with potassium bisulphate andextracted (ethyl acetate). The extract was dried (magnesium sulphate)and evaporated to give3,4-dichloro-2-(N-methyl-ethoxycarbonylamino)benzoic acid (9.38 g) as abrown oil, NMR 1.2(m,3H), 3.1(s,3H), 4.0(m,2H), 7.4(m,1H), 7.9(m,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoic acid as a yellowoil, NMR 1.0 and 1.2(2t,3H), 3.5 and 3.8(2s,3H), 3.6 and 4.1(2q,2H),7.5(m,1H), 7.8(m,2H).

3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoic acid, NMR3.1(s,3H), 3.6 and 3.8(2s,3H), 7.5(m,1H), 7.9(m,1H), 10.0(s,1H).

3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino acid, NMR1.1(m,6H), 1.3(m,2H), 3.2(s,3H), 4.9(m,1H), 7.55(d,1H), 7.9(d,1H).

4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p.195-198° C.

2,4-dibromo-3-ethoxybenzoic acid, m.p. 161-162° C.

4-bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)benzoic acid as anorange solid, m.p. 105-108° C.

2,4-dibromo-3-(2,2,2-trifluoroethoxy)benzoic acid as a white solid, m.p.147-151° C.

4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxybenzoic acid, NMR1.1(m,3H), 3.65(m,8H), 6.3(s,1H), 7.55(d,1H), 7.65(d,1H).

2-(N-ethyl-N-methylsulphonylamino)-3-fluoro-4-(methylthio)benzoic acid,m.p. 129-134° C.

4-chloro-2-(N-ethyl-N-methylsulphonylamino)-3-fluorobenzoic acid, m.p.102.5-100° C.

3,4-dibromo-2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p.110-114° C.

3,4-dichloro-2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p. 87-89°C.

3,4-dichloro-2-(N-propyl-N-methoxycarbonylamino)benzoic acid, NMR(DMSO-D₆) 0.8(t,3H), 1.5(m,2H), 3.2(m,2H), 3.5(s,3H), 7.7(d,1H),7.8(d,1H), 13.5(brd,1H).

3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)benzoic acid, NMR(DMSO-D₆) 1.0(d,3H), 3.45(s,3H), 4.15(m,1H), 7.75(m,2H), 13.0(brd,1H).

3,4-dichloro-2-(N-alkyl-N-methoxycarbonylamino)benzoic acid, NMR(DMSO-D₆) 3.5(s,3H), 4.1(m,2H), 5.05(m,2H), 5.8(m,1H), 7.7(d,1H),7.85(d,1H), 13.35(brd,1H).

3,4-dichloro-2-(N-ethyl-N-propyloxycarbonylamino)benzoic acid, NMR0.68(t,3H), 1.07(t,3H), 1.4(q,2H), 3.5-3.7(m,2H), 3.95(m,2H),7.45(d,1H), 7.87(d,1H), 8.8(brs,1H).

3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoic acid, NMR1.1(m,6H), 3.7(m,2H), 4.13(q,2H), 755(d,1H), 7.92(d,1H), 8.75(brs,1H).

3,4-dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)benzoic acid, NMR1.0(m,9H), 3.5-3.7(m,2H), 4.88(m,1H), 7.48(d,1H), 7.85(d,1H).

3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino)benzoic acid, NMR0.8(t,3H), 1.1(m,5H), 1.45(m,2H), 3.6-3.8(m,2H), 4.05(m,2H),6.45(brs,1H), 7.54(d,1H), 7.93(d,1H).

4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoic acid, m.p. 161-164°C.

4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p.117-119° C.

4-bromo-2-(N-ethyl-N-methylsulphonylamino)-3-(2,2,2-trifluoroethoxy)benzoicacid, m.p. 162-164° C.

4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p. 148-151°C.

2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoic acid, NMR (CD₃CN)1.1(t,3H), 2.95(s,3H), 3.7(q,2H), 7.25(m,2H), 8.0(t, 1H).

2-(N-ethyl-N-methylsulphonylamino)-4-trifluoromethylbenzoic acid, NMR(CD₃CN) 1.1(t,3H), 3.0(s,3H), 3.7(q,2H), 5.7(brs,1H), 7.8(m,2H),8.0(d,1H).

3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoic acid,m.p. 175-176.5° C.

4methyl-2-(N-methyl-N-methylsulphonylamino)benzoic acid m.p. 185-187° C.

4-chloro-2-(N-methylsulphonyl-N-propylamino)benzoic acid, m.p. 133-135°C.

3,4-dichloro-2-(N-methyl-N-methylsulphonylamino)benzoic acid, m.p.118-119.4° C.

2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethylbenzoic acid, m.p.157-160° C.

4-bromo-2-(N-methyl-N-methylsulphonylamino)benzoic acid, m.p. 181-182°C.

3,4-difluoro-2-(N-methyl-N-methylsulphonylamino)benzoic acid, m.p.159.5-161° C.

2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethoxybenzoic acid, m.p.138.5-141° C.

4-chloro-2-(N-isobutyl-N-methylsulphonylamino)benzoic acid, m.p.158-159° C.

4-bromo-2-(N-ethyl-N-methylsulphonylamino)-3-methoxybenzoic acid, NMR1.15(t,3H), 3.1(s,3H), 3.7(m,2H), 4.1(s,3H), 7.65(q,2H).

2-(N-ethyl-N-methylsulphonylamino)-3,4-difluorobenzoic acid, NMR(DMSO-D₆) 1.1(t,3H), 3.1(s,3H), 3.6(q,2H), 7.6(m,1H), 7.75(m,1H).

Reference Example 7

A solution of 3,4 -dichloro-2-(ethoxycarbonylamino)benzoic acid (13.1 g)was stirred with potassium carbonate (26.8 g) in acetone. Methyl iodide(95 ml) was added and the mixture heated at reflux for 2.5 hours, leftat room temperature overnight, filtered and the filtrate evaporated todryness. Purification by chromatography gave methyl3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoate (9.79 g) as abrown oil, NMR 1.0(t,3H), 3.1(2s,3H), 3.8(2s,3H), 4.0(m,2H), 7.4(m,1H)and 7.7(m,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

ethyl 3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoate, NMR1.1(t,3H), 1.38(t,3H), 3.62(s,3H), 3.6(m,2H), 4.36(q,2H), 7.5(d,1H),7.8(d,1H);

methyl 3,4-chloro-2-(N-methyl-N-methoxycarbonylamino)benzoate, NMR3.2(2s,3H), 3.6 and 3.8(2s,3H), 3.9(2s,3H), 7.5(m,1H), 7.8(m,1H);

methyl 3,4-chloro-2-(N-methyl-N-isopropyloxycarbonylamino)benzoate, NMR1.09(m,6H), 3.1(s,3H), 3.8(s3H), 4.9(m,1H), 7.5(m,1H), 7.8(m,1H);

propyl 3,4-chloro-2-(N-propyl-N-methoxycarbonylamino)benzoate, NMR0.83(t,3H), 0.99(t,3H), 1.51(m,2H), 1.75(m,2H), 3.45(m,2H), 3.61(s,3H),4.21(m,2H), 7.5(d,1H), 7.79(d,1H);

isopropyl 3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)benzoate,NMR 1.0(d,3H), 3.6(s,3H), 4.25(m,1H), 5.2(m,1H), 7.5(d,1H), 7.75(d,1H);

allyl 3,4-chloro-2-(N-allyl-N-methoxycarbonylamino)benzoate, NMR3.6(s,3H), 4.2(m,2H), 4.75(m,3H), 5.0(d,3H), 5.9(m,2H), 7.5(d,1H),7.8(d,1H);

ethyl 3,4-dichloro-2-(N-ethyl-N-propyloxycarbonylamino)benzoate, NMR0.75(t,3H), 1.1(t,3H), 1.37(t,3H), 1.5(q,2H), 3.55(m,2H), 3.7(m,2H),4.0(m,2H), 4.35(q,2H), 7.52(d,1H), 7.8(d,1H);

ethyl-3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoate, NMR1.1(m,6H), 1.37(t,3H), 3.5-3.75(m,2H), 4.1(m,2H), 4.37(q,2H), 7.5(d,1H),7.8(d,1H);

ethyl-3,4-dichloro-2-(N-ethyl-N-isopropyloxycarbonylamino)benzoate, NMR1.07(m,9H), 1.37(t,3H), 3.53(m,1H).

ethyl 3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino)benzoate, NMR0.8(t,3H), 1.09(t,3H), 1.16(m,2H), 1.38(t,3H), 1.46(m,2H), 3.56(m,1H),3.7(m,1H), 4.02(m,2H), 4.32(q,2H), 7.5(d,1H), 7.8(d, 1H);

Reference Example 8

A suspension of 2-amino-3,4-dichlorobenzoic acid (10.0 g) in saturatedsodium carbonate solution (80 ml) was diluted with water and filtered.The stirred filtrate was treated by dropwise addition of ethylchloroformate. After 1 hour additional sodium carbonate solution (80 ml)and ethyl chloroformate (9.28 ml) were added and the mixture stirred for1 hour. Potassium bisulphate solution was added to pH2 and the mixtureextracted (ethyl acetate), dried (magnesium sulphate) and evaporated togive 3,4-dichloro-2-ethoxycarbonylaminobenzoic acid (13.14 g), NMR(D₆-DMSO)1.2(t,3H), 4.1(m,2H), 7.6(d,1H), 7.7(d,1H), 9.4(s,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted staring materials:

3,4-dichloro-2-methoxycarbonylaminobenzoic acid, NMR (CD₃CN) 3.7(s,3H),7.5(d,1H), 7.8(d,1H);

methyl bromo-3-ethoxy-2-(N-ethyl-N-methoxycarbonylamino)benzoate, NMR1.1(t,3H), 1.4(t,3H), 3.6(s,3H), 4.0(m,6H), 7.6(s,2H) (n.b. in this casethe methyl ester was obtained rather than the acid);

4-bromo-2-(N-ethyl-Nmethoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)benzoic acid, NMR(DMSO-D₆) 1.0(t,3H), 1.4(s,3H), 1.5(s,2H), 3.6(m,2H), 3.7(s,1H),4.35(m,1H), 4.6(m,1H), 7.65(s,2H);

methyl 4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-methoxybenzoate, NMR1.1(m,3H), 3.6(m,4H), 3.8(m,6H), 3.9(m,2H), 7.6(s,2H) (n.b. in this casethe methyl ester was obtained rather than the acid);

3,4-dichloro-2-propyloxycarbonylaminobenzoic acid, m.p. 156-160° C.;

3,4-dichloro-2-isopropyloxycarbonylaminobenzoic acid, m.p. 188-190° C.;

2-n-butyloxycarbonylamino-3,4-dichlorobenzoic acid, m.p. 128-130° C.

Reference Example 9

Magnesium (3.0 g) was stirred in methanol, carbon tetrachloride (0.5 ml)added and the mixture warmed at 50° C. until the metal had dissolved(1.5 hours). Tert-butyl 3-cyclopropyl-3-oxopropanoate (20.0 g) was thenadded dropwise and the mixture heated under reflux conditions for 1hour. The solvent was evaporated and re-evaporated after addition oftoluene to give tert-butyl 3-cyclopropyl-3-oxopropanoate magnesium salt(29.9 g) as a white solid, m.p. >300° C., IR max (C═O) 1520, 1540; (C—O)1350 cm−1.

Reference Example 10

A mixture of4-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole(0.5 g) and concentrated sulphuric acid (6 ml) in acetic acid (9 ml) washeated at 70° C. for 4 hours, then at 90° C. for 4 hours. The mixturewas poured into excess water and carefully brought to pH 5.5 by theaddition of 2M sodium hydroxide solution. extracted with ethyl acetate,dried (anhydrous magnesium sulphate), evaporated and purified by columnchromatography to yield4-[4-bromo-3-ethoxy-2-(methylamino)benzoyl]-5-cyclopropylisoxazole(0.096 g), NMR 1.15(m,2H), 1.25(m,2H), 1.4(t,3H), 2.5(m,1H), 2.9(s,3H),3.9(q,2H), 6.8(d,1H), 7.05(d,1H), 7.1(s,1H), 8.25(s,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

4-[4-chloro-2-(methylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.1(m,2H), 1.2(m,2H), 2.3(m,1H), 2.9(m,3H), 6.5(q,1H), 6.6(d,1H),7.4(d,1H), 8.2(s,1H), 8.4(brs,1H);

4-[3,4-difluoro-2-(methylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.2(m,2H), 1.3(m,2H), 2.45(m,1H), 3.2(m,3H), 6.45(m,1H), 73(m,1H),8.2(s,1H), 8.3(s,1H);

4-[4-chloro-2-(ethylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.2(m,2H), 1.3(m,5H), 2.4(m,1H), 3.2(m,2H), 6.6(d,1H), 6.7(s,1H),7.5(d,1H), 8.3(s,1H), 8.45(s,1H);

4-[4-chloro-2-(propylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.05(t,3H), 1.21(m, 2H), 1.3(m,2H), 1.8(q,2H), 2.45(m,1H), 3.2(m,2H),6.6(d,1H), 7.5(d,1H), 8.3(s,1H), 8.6(s,1H);

5-cyclopropyl-4-(2-ethylamino-4-fluorobenzoyl)isoxazole, NMR 1.2(m,2H),1.35(m,5H), 2.4(m,1H), 3.25(m,2H), 6.3(m,2H), 7.6(h,1H), 8.4(s,1H),8.6(s,1H),

5-cyclopropyl-4-(2-ethylamino-4-trifluoromethylbenzoyl)isoxazole, NMR1.2(m,2H), 1.35(m,5H), 2.5(m,1H), 3.3(m,2H), 6.8(d,1H), 7.0(s,1H),7.7(d,1H), 8.3(s,1H), 8.35(s,1H);

5-cyclopropyl-4-(2-methylamino-4-trifluoromethylbenzoyl)isoxazole, NMR1.1(m,2H), 1.2(m,2H), 2.4(m,1H), 2.9(d,3H), 6.8(q,1H), 6.9(s,1H),7.6(d,1H), 8.2(s,2H);

4-[4-bromo-2-(methylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.1(m,2H), 1.2(m,2H), 2.4(m,1H), 2.8(s,3H), 6.6(q,1H), 6.8(s,1H),7.3(d,1H), 8.2(s,2H);

5-cyclopropyl-4-[4-iodo-2-(methylamino)benzoyl]isoxazole, NMR 1.1(m,2H),1.2(m,2H), 2.3(m,1H), 2.8(s,3H), 6.9(q,1H), 7.1(s,1H), 7.2(d,1H),8.2(s,2H);

5-cyclopropyl-4-(2-methylamino-4-trifluoromethoxybenzoyl)isoxazole, NMR1.1(m,2H), 1.2(m,2H), 2.4(m,1H), 2.9(d,3H), 6.4(q,1H), 6.5(s,1H),7.5(d,1H), 8.2(s,1H), 8.5(brs,1H);

4-[4-chloro-2(isobutylamino)benzoyl]-5-cyclopropylisoxazole, NMR0.9(d,6H), 1.1(m,2H), 1.2(m,2H), 1.9(m,1H), 2.4(m,1H), 3.0(t,2H),6.4(q,1H), 6.5(s,1H), 7.4(d, 1H), 8.2(s,1H), 8.6(s,1H);

4-[3,4-dichloro-2-(methylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.2(m,2H), 1.3(m,2H), 2.6(m,1H), 2.8(s,3H), 5.6(brs,1H), 6.8(d,1H),7.2(d,1H), 8.12(s,1H);

5-cyclopropyl-4-[4-methyl-2-(methylamino)benzoyl]isoxazole, NMR1.1(m,2H), 1.2(m,2H), 2.2(s,3H), 2.3(m,1H), 2.8(s,3H), 6.3(q,1H),6.5(s,1H), 7.4(d,1H), 8.2(s,1H), 8.9(brs,1H);

5-cyclopropyl-4-(2-ethylamino-4-methylsulphonylbenzoyl)isoxazole, NMR1.1(m,2H), 1.2(m,5H), 2.5(m,1H), 3.0(s,3H), 3.2(m,2H), 7.0(d,1H),7.2(m,1H), 7.6(d,1H), 8.2(brs,1H), 8.3(s,1H);

5-cyclopropyl-4-[(2-ethylamino)benzoyl]isoxazole, NMR 1.15(m,2H),1.3(m,2H), 1.35(t,3H), 2.45(m,1H), 3.3(q,2H), 6.6(dt,1H), 6.75(d,1H),7.4(m,1H), 7.55(dd,1H), 83(s,2H);

4-[3-chloro-2-ethylamino-4-(methylthio)benzoyl]-5-cyclopropylisoxazole,NMR 1.2(t,3H), 1.25(m,2H), 1.35(m,2H), 2.5(s,3H), 2.65(m,1H),3.15(m,2H), 5.6(brs,1H), 6.6(d,1H), 7.35(d,1H), 8.3(s,1H);

5-cyclopropyl-4-(2-ethylamino-3,4-difluorobenzoyl)isoxazole, NMR1.2(m,2H), 1.3(m,5H), 2.45(m,1H), 3.6(m,2H), 6.4(m,1H), 7.3(m,1H),8.2(brs,1H), 8.3(s,1H);

5-cyclopropyl-4-[2-ethylamino-3-fluoro-4-(methylthio)benzoyl]isoxazole,NMR 1.2(m,2H), 1.25(t,3H), 1.3(m,2H), 2.5(m,4H), 3.55(m,2H),6.45(dd,1H), 7.3(dd,1H), 8.0(brs,1H), 8.3(s,1H);

4-(4-chloro-2-ethylamino-3-fluorobenzoyl)-5-cyclopropylisoxazole, m.p.105.5-107° C.;

4-[3,4-dibromo-2-(ethylamino)benzoyl]-5-cyclopropylisoxazole, m.p.93-95° C.;

4-[3-chloro-2-(ethylamino)benzoyl]-5-cyclopropylisoxazole, NMR1.15(t,3H), 1.25(m,4H), 2.7(m,1H), 3.1(m,2H), 5.25(s,1H), 6.8(t,1H),7.3(d,1H), 7.45(d,1H), 8.3(s,1H).

Reference Example 11

A suspension of4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl chloride(2.45 g) in toluene (35 ml) was added to a solution of tert-butyl3-cyclopropyl-3-oxopropionate magnesium enolate (1.3 g) in toluene (15ml) and stirred for 2 days. Trifluoroacetic acid (1.1 ml) was added andthe mixture was warmed at 65° C. for 1.5 hours, then cooled, washed withwater, the organic extract dried (anhydrous magnesium sulphate) and thesolvent evaporated. Purification by chromatography gave1-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione(1.87 g) as a yellow semi-solid, NMR 1.05(m,2H), 1(m,2H), 1.5(t,3H),1.75(m,1H), 3.0(s,3H), 3.3(s,3H), 4.2(brm,2H), 6.1(s,1H), 7.15(d,1H),7.6(d,1H), 15.9(brs,1H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

1-[4-bromo-2-(N-methyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,m.p. 120-122° C.;

1-[4-chloro-2-(N-isobutyl-N-methylsulphonylamino)phenyl]-3-cyclopropylpropane-1,3-dione,NMR 0.9(m,6H), 1.01(m,2H), 1.25(m,2H), 1.8(m,1H), 3.05(s,3H),3.45(brs,2H), 6.1(s,1H), 7.3(m,3H), 16.1(brs,1H);

3-cyclopropyl-1-[3,4-difluoro-2-(N-methyl-N-methylsulphonylamino)phenyl]propane-1,3-dione.

Reference Example 12

4-Bromo-3-ethoxy-2-(N-methylsulphonylamino)benzoic acid (2.83 g) wasadded to a suspension of potassium carbonate (7.0 g) in dry acetone andheated under reflux for 1.25 hours. Methyl iodide (6.2 ml) was added andthe mixture was heated for a further 45 hours. The cooled mixture wasfiltered and the filtrate evaporated. After addition of dichloromethane,the solution was washed with sodium bicarbonate solution, water, dried(anhydrous magnesium sulphate) and the solvent evaporated to give methyl4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoate (2.91 g),m.p. 82-88° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate, NMR1.2(t,3H), 1.4(t,3H), 3.0(s,3H), 3.7(m,2H), 4.4(q,2H), 7.15(m,2H),8.0(t,1H);

ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-trifluoromethylbenzoate,

propyl 4-chloro-2-(N-methylsulphonyl-N-propylamino)benzoate m.p. 81-83°C.;

ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate m.p.108.6-109.4° C.;

methyl 2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethylbenzoate,NMR 2.93(s,3H), 3.3(s,3H), 3.9(s,3H), 7.65(m,2H), 8.0(dd, 1H);

methyl 4-bromo-2-(N-methyl-N-methylsulphonylamino)benzoate, NMR2.95(s,3H), 3.23(s,3H), 3.83(s,3H), 7.5(dd,1H), 7.58(d,1H), 7.75(d,1H);

methyl 4-methyl-2-(N-methyl-N-methylsulphonylamino)benzoate m.p.100-103° C.;

methyl 3,4-difluoro-2-(N-methyl-N-methylsulphonylamino)benzoate as anorange solid, NMR 3.01(s,3H), 3.3(s,3H), 3.91(s,3H), 7.24(q,1H),7.73(m,1H).

Reference Example 13

Methanesulphonamide (1.05 g) was added to a suspension of sodium hydride(60% oil dispersion, 1.36 g) in dry dioxan. 2,4-Dibromo-3-ethoxybenzoicacid (4.0 g) was added, followed by copper (I) bromide (0.16 g) and themixture was heated under reflux for 15 hours. The cooled mixture wasconcentrated, 2M hydrochloric acid solution added, and extracted withethyl acetate. The organic phase was washed (water) dried (anhydrousmagnesium sulphate) and the solvent evaporated to give, aftertrituration with ether,4-bromo-3-ethoxy-2-(N-methylsulphonylamino)benzoic acid (3.44 g) as awhite solid, NMR (DMSO-D₆) 1.4(t,3H), 3.2(s,3H), 3.3(brs,1H),4.05(q,2H), 7.6(q,2H).

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

4-bromo-2-(N-methylsulphonylamino)-3-methoxybenzoic acid, m.p. 181-188°C.;

4-fluoro-2-(N-methylsulphonylamino)benzoic acid (employing copper (I)chloride in place of copper (I) bromide);

4-bromo-2-(N-methylsulphonylamino)-3-(2,2,2-trifluoroethoxy)benzoic acidas a white solid, m.p. 191-193° C.;

3-chloro-4-fluoro-2-(N-methylsulphonylamino)benzoic acid, m.p.157.5-161.5° C.;

3,4-difluoro-2-(N-methylsulphonylamino)benzoic acid, NMR (DMSO-D₆)3.2(s,3H), 6.8(brs,1H), 7.4(m,1H), 7.75(m,1H);

4-chloro-3-fluoro-2-(N-methylsulphonylamino)benzoic acid, m.p.148-159.8° C. (containing some 4-chloro-3-fluorobenzoic acid);

3,4-dibromo-2-(N-methylsulphonylamino)benzoic acid, NMR (DMSO-D₆)3.1(s,3H), 7.65(d,1H), 7.8(d,1H), 9.75(s,1H);

3-chloro-2-(N-methylsulphonylamino)benzoic acid, NMR (DMSO-D₆)3.05(s,3H), 6.8(s,1H), 7.35(t,1H), 7.7(m,2H);

4-chloro-2-(N-methylsulphonylamino)benzoic acid, m.p. 188-192° C. from2-bromo-4-chlorobenzoic acid, employing copper (I) bromide andmethanesulphonamide and 3 equivalents of sodium hydride.

Also, by proceeding in a similar manner replacing methanesulphonamidewith the appropriate N-alkylmethanesulphonamide the following compoundswere prepared from the appropriately substituted starting materials:

4-iodo-2-(N-methyl-N-methylsulphonylamino)benzoic acid. m.p. 174-175° C.from 2-chloro-4-iodobenzoic acid;

2-(N-ethyl-N-methylsulphonylamino)benzoic acid, m.p. 116-118.5° C.(starting from 2-bromobenzoic acid).

Reference Example 14

Ethyl 2,4-dibromo-3-hydroxybenzoate (5.0 g) was added to a stirredsuspension of potassium carbonate (106.4 g) in dry N,N-diethylformamide(DMF). A solution of iodomethane (25.7 g) in DMF was added over 18minutes, and the resulting mixture was heated at 85° C. for 1.3 hours.The cooled mixture was poured onto water and extracted with ether. Theextract was washed (brine solution), dried (anhydrous magnesiumsulphate) and the solvent evaporated in vacuo to give ethyl2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H),4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).

Reference Example 15

A mixture of concentrated sulphuric acid (128 ml) and acetic acid (192ml) was added with stirring to4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoic acid (8.8 g)at 85° C. for 100 minutes and left to stand at ambient temperature for 3days. After pouring onto excess water, the mixture was made neutral bythe careful addition of sodium hydroxide solution with cooling&g,extracted with ethyl acetate, dried (anhydrous magnesium sulphate) andthe solvent evaporated to give 4-bromo-2-ethylamino-3-ethoxybenzoic acid(4.74 g) as a brown solid, m.p. 129-139° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted staring materials:

4-bromo-2-ethylamino-3-(2,2,2-trifluoroethoxy)benzoic acid, m.p.179-180° C.;

4-bromo-2-ethylamino-3-methoxybenzoic acid, m.p. 129-135° C.

Reference Example 16

A solution of 4-bromo-3-ethoxy-2-(N-methylsulphonylamino)benzoic acid(10 g) in DMF was added to a stirred suspension of sodium hydride (3.55g of a 60% oil dispersion) in DMF at 0° C. The mixture was slowly heatedto 85° C., maintained at that temperature for 1 hour, cooled to 0° C.and ethyl iodide (27.7 g) added. After heating at 85° C. overnight. thecooled mixture was treated with ammonium chloride solution and extractedwith ether. The extract was washed (brine solution), dried (anhydrousmagnesium sulphate) and the solvent evaporated to give a brown gum whichwas purified by chromatography to yield ethyl4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoate (3.4 g),m.p. 43-45° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

ethyl4-bromo-2-(N-ethyl-N-methylsulphonylamino)-3-(2,2,2-trifluoroethoxy)benzoateas a white solid, m.p. 57-59° C.

ethyl 4-bromo-2-(N-ethyl-N-methylsulphonylamino)-3-methoxybenzoate, m.p.69-72° C.;

ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate, m.p.76-79° C.;

ethyl 2-(N-ethyl-N-methylsulphonylamino)-3,4-difluorobenzoate, NMR1.2(t,3H), 1.4(t,3H), 3.0(s,3H), 3.7(q,2H), 4.4(q,2H), 7.25(m,1H),7.75(m,1H);

ethyl 4-chloro-2-(N-ethyl-N-methylsulphonylamino)-3-fluorobenzoate, NMR1.2(t,3H), 1.4(t,3H), 3.0(s,3H), 3.7(q,2H), 4.4(q,2H), 7.5(d,1H),7.7(d,1H);

ethyl 3,4-dibromo-2(N-ethyl-N-methylsulphonylamino)benzoate, NMR1.2(t,3H), 1.4(t,3H), 3.1(s,3H), 3.8(m,2H), 4.4(m,2H), 7.7(s,2H);

ethyl 3chloro-2-(N-ethyl-N-methylsulphonylamino)benzoate, NMR1.15(t,3H), 1.3(t,3H), 3.0(s,3H), 3.75(m,2H), 4.3(m,2H), 7.3(t,1H),7.55(d,1H), 7.75(d,1H).

Reference Example 17

A mixture of ethyl 2,4-dibromo-3-hydroxybenzoate (5.0 g) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was added toa stirred mixture of sodium hydride (60% oil dispersion, 0.617 g) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone under an inertatmosphere. The mixture was heated at 140° C. for 1 hour, cooled and2,2,2-trifluoroethylpara-toluenesulphonate (4.71 g) was added. Afterheating at 140° C. for 18 hours, further2,2,2-trifluoroethylpara-toluenesulphonate (4.71 g) was added, and themixture was heated at 140° C. for 3 days. The cooled mixture was thenpoured onto water, extracted with ether, and the extract washed in turnwith sodium hydroxide solution, water and brine. The extract was thendried (anhydrous magnesium sulphate) and the solvent evaporated to giveethyl 2,4-dibromo-3-trifluoethoxybenzoate (8.27 g), NMR 1.3(t,3H),4.3(q,2H), 4.4(m,2H), 7.4(d,1H), 7.5(d,1H).

Reference Example 18

A solution of methanethiol (4 ml) in dry DMF was added to a mixture ofethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate (7.4g) and anhydrous potassium carbonate (4.71 g) in DMF at 40° C. Themixture was maintained at −10° C. for 1 hour, then warmed to ambienttemperature over 2.5 hours. Water was added and the mixture extractedwith ether, washed with brine solution then water, dried (anhydrousmagnesium sulphate) and the solvent evaporated to give ethyl3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoate (8.3g) as a white powder, m.p. 109-110.5° C.

By proceeding in a similar manner ethyl2-(N-ethyl-N-methylsulphonylamino)-3-fluoro-(methylthio)benzoate wasprepared, m.p. 70.5-73.5° C.

Reference Example 19

n-Butyl lithium (25M solution, 76 ml) was added to a stirred solution ofdiisopropylamine (28 ml) in dry tetrahydrofuran (THF) at −75° C., andmaintained at −30° C. for a further 1 hour, to produce lithiumdiisopropylamide (LDA). After re-cooling to −75° C., a solution of 3-chloro-4-fluorobenzoic acid (14.4 g) in dry THF was added over 1 hour,and stirring was continued overnight at −75° C. A solution of1,2-dibromotetrachloroethane (42.77 g) in dry THF was then added over 20minutes, stirring was continued for 2 hours at −70° C. then at roomtemperature for 4 hours. Water was added, the organic and aqueous phaseswere separated and the aqueous phase was washed with ether, thenacidified with hydrochloric acid solution and extracted withdichloromethane. The dichloromethane extract was dried (anhydrousmagnesium sulphate) and the solvent evaporated to give2-bromo-3-chloro-4-fluorobenzoic acid (19.54 g) as a beige solid, NMR(DMSO-D₆) 7.55(t,1H), 7.75(dd,1H), 13.8(brs,1H).

By proceeding in a similar manner 2,3,4-tribromobenzoic acid wasprepared, NMR (DMSO-D₆) 7.5(d,1H), 7.9(d,1H), 13.75(brs,1H).

Also, by proceeding in a similar manner but employing n-butyl lithium inplace of LDA the following compounds were prepared:

2-bromo-3,4-difluorobenzoic acid, m.p. 162-170° C.,

2-bromo-3-fluorobenzoic acid, NMR (DMSO-D₆) 7.55(dd,1H), 7.8(dd,1H).

Reference Example 20

3,4-Dichloroanthranilic acid (61.8 g) was stirred in THF at −15° C., andtriethylamine was added. Methyl chloroformate (36.9 g) was then added at−15° C. and the mixture stirred for 45 minutes. Water was then added,followed by concentrated hydrochloric acid solution until pH 1 wasachieved, and the solution was stirred overnight. Excess water was addedand the mixture was extracted with ethyl acetate. The extract was washedwith water, dried (anhydrous magnesium sulphate) and the solventevaporated The resulting solid was recrystallised from a solution oftoluene and cyclohexane to give3,4-dichloro-2-(methoxycarbonylamino)benzoic acid (65.1 g) as a fawnsolid, m.p. 155-156° C.

Reference Example 21

Potassium carbonate (1.25 g) was added to a stirred solution of methyl4-chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in acetone. Themixture was stirred for 15 minutes and methyl iodide (8.0 g) was added.The resultant mixture was stirred at room temperature for 1 hour andleft to stand overnight The mixture was evaporated to dryness and theresidue was dissolved in ethyl acetate and washed with sodium hydroxidesolution (2M) and water, dried (anhydrous magnesium sulphate) andfiltered. The filtrate was evaporated to dryness to give methyl4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoate (4.9 g) as a whitesolid, m.p. 73-75° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

ethyl 4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoate, NMR 1.1(t,3H)135(t,3H) 2.9(s,3H) 3.65(q,2H) 4.3(q,2H) 7.3(d,1H) 7.35(s,1H) 7.8(d,1H);

methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonylamino)benzoate, NMR2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H), 7.71(d,1H);

methyl 2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethylbenzoate,NMR 2.95(s,3H), 3.3(s,3H), 3.95(s,3H), 7.25(m,2H), 8.0(d,1H);

methyl 4-dichloro-2-(N-isobutyl-N-methylsulphonylamino)benzoate, m.p.89-90° C., employing isobutyl iodide instead of methyl iodide.

Referee Example 22

A solution of methanesulphonyl chloride (6.3 g) in dichloromethane wasadded to a stirred, cooled (0-5° C.) solution of methyl 2-aminochlorobenzoate (9.5 g) in dichloromethane. Triethylamine (7.1 g) wasthen added and the mixture was stirred at 0-5° C. for 10 minutes andthen at room temperature for 0.5 hours. The mixture was diluted with 2Nhydrochloric acid. The organic phase was separated, washed with water,dried and evaporated. The crude product was purified by columnchromatography to yield methyl4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid, (3.6 g)m.p. 125.5-128.1° C.

Reference Example 23

A mixture of 2-amino-4-methylbenzoic acid (15.0 g) and concentratedsulphuric acid (20 ml) was heated under reflux with methanol for 18hours. After removal of the solvent the residue was dissolved indichloromethane, basified with sodium carbonate solution and the organicphase was washed with water, dried (anhydrous magnesium sulphate) andthe solvent evaporated to give methyl 2-amino-4-methylbenzoate, m.p.41-43° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

methyl 3,4-dichloro-2-(N-methyl-N-methylsulphonylamino)benzoate, NMR2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H), 7.71(d,1H);

methyl 2-amino-4-trifluoromethylbenzoate m.p. 60-62° C.;

methyl 2-amino-3,4-difluorobenzoate.

Reference Example 24

An aqueous solution of sodium hydroxide (11.0 g) was added to a solutionof a mixture of methyl4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl4-methyl-2-(N-methylsulphonylamino)benzoate (2326 g) in methanol and theresulting suspension was heated at reflux for 1 hour. It was cooled andthe methanol was removed by evaporation. The aqueous solution wasacidified and the resultant solid was filtered off to give4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a creamsolid, m.p. 202-205° C.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

4-bromo-2-(N-methylsulphonylamino)benzoic acid m.p. 178-186° C.;

2-(N-methylsulphonylamino)-4-trifluoromethylbenzoic acid.

Reference Example 25

Methanesulphonyl chloride (12.2 ml) was added to a stirred, cooledsolution of methyl 2-aminomethylbenzoate (103 g) and triethylamine (193ml) in dichloromethane while maintaining the temperature below 0° C. Themixture was stirred at room temperature for 4 hours. Hydrochloric acidsolution (2M) was added and the layers were separated. The organic layerwas washed with water, dried (magnesium sulphate) and filtered. Thefiltrate was evaporated to dryness to give a mixture of methyl4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl4-methyl-2-(N-methylsulphonylamino)benzoate (18.26 g) as a yellow solidwhich was not further purified.

By proceeding in a similar manner the following compounds were preparedfrom the appropriately substituted starting materials:

methyl 2-[N,N-bis(methylsulphonyl)amino]-4-trifluoromethylbenzoate m.p.159-163° C.;

methyl 4-bromo-2-[N,N-bis(methylsulphonyl)amino]benzoate, m.p. 221-225°C.;

methyl 3,4-difluoro-2-[N,N-bis(methylsulphonyl)amino]benzoate as asolid, NMR 3.42(s,6H), 3.87(s,3H), 73(q,1H), 7.79(m,1H);

methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonyl benzoate m.p.207.4-211.2° C.;

methyl 2-(N-methylsulphonylamino)-4-trifluoromethoxybenzoate and methyl2-[N,N-bis(methylsulphonyl)amino]-4trifluoromethoxybenzoate.

Reference Example 26

A mixture of ethyl2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate (1.4 g) andlithium hydroxide monohydrate (1.37 g) in aqueous ethanol (50%) wasstirred at room temperature for 19 hours. The mixture was then acidifiedwith conc. hydrochloric acid and extracted with ethyl acetate. Thecombined organic extracts were dried (magnesium sulphate), filtered andevaporated to yield2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoic acid as abrown solid (9.48 g), NMR (acetone-d₆); 1.15(t,3H), 2.98(s,3H),322(s,3H), 3.85(q,2H), 8.0-8.25(m,3H).

Reference Example 27

A suspension of methyl2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) andlithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) wasstirred at room temperature for 18 hours. The resulting solution wasacidified with concentrated hydrochloric acid and extracted with ethylacetate. The combined organic extracts were dried (magnesium sulphate),filtered and evaporated to yield2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid,NMR (acetone d₆); 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).

By proceeding in a similar manner3,4-difluoro-2-(N-methylsulphonylamino)benzoic add was prepared as abrown solid.

Reference Example 28

Concentrated hydrochloric acid (90 ml) was added to a stirred suspensionof methyl 2-nitro-4-methylsulphonylbenzoate (25 g) in methanol at −5° C.(ice/salt bath). The cooling bath was then removed and iron dust (175 g)was added portionwise over a period of 20 minutes. The resultingexotherm was controlled using a cooling bath so that the temperature didnot exceed 50° C. After 15 minutes of cooling, the bath was removed andthe reaction mixture was allowed to reach room temperature. Stirring wascontinued for a further 3 hours. The mixture was poured onto ice andthen neutralised with sodium carbonate. Dichloromethane was added andthe suspension was filtered. The filtrate was extracted with furtherdichloromethane and the combined organic extracts were dried (magnesiumsulphate), filtered and evaporated to yield a crude product which waspurified by recrystallisation from ethyl acetate/hexane to give methyl2-amino-4methylsulphonylbenzoate (45 g) as yellow needles, m.p.98.3-98.5° C.

Reference Example 29

A mixture of methyl 2-amino-3,4-dichlorobenzoate (2.2 g) andmethanesulphonyl chloride (2.86 g) was stirred at 100° C. for 4 hours. Afurther quantity of methanesulphonyl chloride (2.86 g) was added and themixture was stirred at 100° C. overnight. The mixture was poured intowater then extracted with ethyl acetate. The combined organic extractswere washed with water, dried (magnesium sulphate) and evaporated toyield a brown oil which was crystallised from cyclohexane/ethyl acetateto yield methyl 3,4-dichloro-2-(methylsulphonylamino)benzoate as lightbrown crystals (1.4 g), m.p. 100-102° C.

Reference Example 30

6,7-Difluoroisatin (22.2 g) was added to a solution of sodium hydroxide(2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was added at 40° C. or lessover 20 minutes. After 1 hour the mixture was heated to 65° C. for 0.5hours, cooled, poured onto water and acidified with concentratedhydrochloric acid. The resulting solid was filtered, washed with waterand recrystallised from ethyl acetate/cyclohexane to give2-amino-3,4-difluorobenzoic acid (11.3 g) as an orange solid, m.p.207-208° C.

Reference Example 31

2,3-Difluoro-α-isonitrosoacetanilide (36.8 g) was added during 1 hour toa stirred solution of concentrated sulphuric acid and water at 65-75° C.After an additional 20 minutes at 80° C., the cooled mixture was pouredonto excess ice-water. Extraction with ethyl acetate was followed bywater washing, drying (magnesium sulphate) and evaporation to dryness togive a brown solid. Trituration with boiling cyclohexane gave aftercooling, 6,7-difluoroisatin (22.2 g), m.p. 1645-167° C. as a brownsolid.

Reference Example 32

Chloral hydrate (38.9 g) was added to a stirred solution of sodiumsulphate (219 g) in water. A solution of 2,3-difluoroaniline (25 g) in amixture of concentrated hydrochloric acid (19.4 ml) and water (1 17 ml)was added. A solution of hydroxylamine hydrochloride (41.35 g) in waterwas then added over 35 minutes and the mixture stirred for 1 hour at95-100° C. After cooling the solid was filtered, washed with water, thenwith petroleum ether and dried in a desiccator to furnish2,3-difluoro-α-isonitrosoacetanilide (36.8 g), m.p. 124.5-125° C.

Reference Example 33

A solution of sodium hydroxide (2.38 g) in water was added to a mixtureof methyl 2-(N-methylsulphonylamino)-4trifluoromethoxybenzoate andmethyl 2-[N,N-bis(methylsulphonyl)amino]-4trifluoromethoxybenzoate (8.26g) in methanol at 15-20° C. After an additional 15 minutes the solid wasfiltered, dissolved in ethyl acetate, dried (magnesium sulphate) andevaporated in vacuo to give methyl2-(N-methylsulphonylamino)-4trifluoromethoxybenzoate as a brown solid(4.15 g) after trituration with hexane, NMR 3.0(s,3H), 3.9(s,3H),6.9(m,1H), 7.55(m,1H), 8.05(d,1H), 10.5(brs,1H).

Reference Example 34

By following the procedure described in Example 1 above the followingcompounds were prepared from the appropriately substituted startingmaterials:

4-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 97-99° C.;

4-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 114-115.8° C.,

5-cyclopropyl-4-[4-methyl-2-(N-methyl-N-methylsulphonylamino)benzoyl]isoxazole,m.p. 120-122° C.;

4-[4-chloro-2-(N-propyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 127-128° C.;

5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoyl]isoxazole,m.p. 171-172° C.;

4-[3,4-dichloro-2-(N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 153-154° C.;

4-[4-bromo-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 128-130° C.;

4-[3,4-difluoro-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 134-136° C.;

4-[4-iodo-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 128-129° C.; and

4-[2-(N-isobutyl-N-methylsulphonylamino)-4-chlorobenzoyl]-5-cyclopropylisoxazole,m.p. 118-118.5° C.

Reference Example 35

By following the procedure described in Example 2 above the followingcompounds were prepared from the appropriately substituted startingmaterials:

5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoyl]isoxazole,NMR 1.25(t,3H), 1.35(m,2H), 2.6(m1H), 3.0(s,3H), 3.7(q,2H), 7.2(m,2H),7.5(t,1H), 8.2(s,1H).

5cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)-4-trifluoromethylbenzoyl]isoxazole,NMR 1.0(m,5H), 1.1(m,2H), 2.5(m,1H), 2.7(s,3H), 3.5(q,2H), 7.4(d,1H),7.5(m,2H), 8.0(s,1H).4-[4-chloro-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropyl-isoxazole,m.p. 128.3-130.8° C.

5-cyclopropyl-4-[f2-(N-methyl-N-methylsulphonylamino)-4trifluoromethylbenzoyl]isoxazole, NMR 1.2-15(m,4H), 2.65(m,1H),2.95(s,3H), 3.3(s,3H), 7.6(dd,1H), 7.75(m,2H), 8.2(s,1H).

5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonylamino)-4-trifluoromethoxybenzoyl]isoxazole,NMR 1.15(m,2H), 1.25(m,2H), 2.6(m,1H), 2.9(s,3H), 3.2(s,3H), 7.2(m,2H),7.5(d,1H), 8.1(s,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)benzoyl]isoxazole,m.p. 116-117.5° C.

4-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoyl]-5-cyclopropyl-isoxazole,m.p.101-102° C.

5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)-3,4-difluorobenzoyl]isoxazole,NMR 1.2(m,5H), 1.3(m,2H), 2.6(m,1H), 2.95(s,3H), 3.7(m,2H), 7.2(m,2H),8.1(s,1H).

5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonylamino)-3-fluoro-4-(methylthio)benzoyl]isoxazole,m.p. 118.5-120.5° C.

4-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)-3-fluorobenzoyl]-5-cyclopropylisoxazole,m.p. 126-128.5° C.

4-[3,4-dibromo-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 169.5-171° C.

4-[3-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole,m.p. 140-142° C.

According to a feature of the present invention, there is provided amethod for controlling the growth of weeds (i.e. undesired vegetation)at a locus which comprises applying to the locus a herbicidallyeffective amount of at least one isoxazole derivative of formula (I) oran agriculturally acceptable salt thereof. For this purpose, theisoxazole derivatives are normally used in the form of herbicidalcompositions (i.e. in association with compatible diluents or carriersand/or surface active agents suitable for use in herbicidalcompositions), for example as hereinafter described. The compounds offormula (I) show herbicidal activity against dicotyledonous (i.e.broad-leafed) and monocotyledonous (i.e. grass) weeds by pre- and/orpost-emergence application. By the term “pre-emergence application” ismeant application to the soil in which the weed seeds or seedlings arepresent before emergence of the weeds above the surface of the soil. Bythe term “post-emergence application” is meant application to the aerialor exposed portions of the weeds which have emerged above the surface ofthe soil. For example, the compounds of formula (I) may be used tocontrol the growth of:

broad-leafed weeds, for example, Abutilon theophrasti, Amaranthusretroflexus, Bidens pilosa, Chenopodium album, Galium aparine, Ipomoeaspp. e.g. Ipomoea purpurea, Sesbania exaltata, Sinapis arvensis, Solanumnigrum and Xanthium strumarium, and

grass weeds, for example Alopecurus myosuroides, Avena fatua, Digitariasanguinalis, Echinochloa crus-galli, Sorghum bicolor, Eleusine indicaand Setaria spp, e.g. Setaria faberii or Setaria viridis, and

sedges, for example, Cyperus esculentus.

The amounts of compounds of formula (I) applied vary with the nature ofthe weeds, the compositions used, the time of application, the climaticand edaphic conditions and (when used to control the growth of weeds incrop-growing areas) the nature of the crops. When applied to acrop-growing area, the rate of application should be sufficient tocontrol the growth of weeds without causing substantial permanent damageto the crop. In general, taking these factors into account, applicationrates between 0.01 kg and 5 kg of active material per hectare give goodresults. However, it is to be understood that higher or lowerapplication rates may be used, depending upon the particular problem ofweed control encountered.

The compounds of formula (I) may be used to control selectively thegrowth of weeds, for example to control the growth of those specieshereinbefore mentioned, by pre- or post-emergence application in adirectional or non-directional fashion, e.g. by directional ornon-directional spraying, to a locus of weed infestation which is anarea used, or to be used, for growing crops,. for example cereals, e.g.wheat, barley, oats, maize and rice, soya beans, field and dwarf beans,peas, lucerne, cotton, peanuts, flax, onions, carrots, cabbage, oilseedrape, sunflower, sugar beet, and permanent or sown grassland before orafter sowing of the crop or before or after emergence of the crop. Forthe selective control of weeds at a locus of weed infestation which isan area used, or to be used, for growing of crops, e.g. the cropshereinbefore mentioned, application rates between 0.01 kg and 4.0 kg,and preferably between 0.01 kg and 2.0 kg, of active material perhectare are particularly suitable.

The compounds of formula (I) may also be used to control the growth ofweeds, especially those indicated above, by pre- or post-emergenceapplication in established orchards and other tree-growing areas, forexample forests, woods and parks, and plantations, e.g. sugar cane, oilpalm and rubber plantations. For this purpose they may be applied in adirectional or non-directional fashion (e.g. by directional ornon-directional spraying) to the weeds or to the soil in which they areexpected to appear, before or after planting of the trees or plantationsat application rates between 0.25 kg and 5.0 kg, and preferably between0.5 kg and 4.0 kg of active material per hectare.

The compounds of formula (I) may also be used to control the growth ofweeds, especially those indicated above, at loci which are notcrop-growing areas but in which the control of weeds is neverthelessdesirable.

Examples of such non-crop-growing areas include airfields, industrialsites, railways, roadside verges, the verges of rivers, irrigation andother waterways, scrublands and allow or uncultivated land, inparticular where it is desired to control the growth of weeds in orderto reduce fire risks. When used for such purposes in which a totalherbicidal effect is frequently desired, the active compounds arenormally applied at dosage rates higher than those used in crop-growingareas as hereinbefore described. The precise dosage will depend upon thenature of the vegetation treated and the effect sought.

Pre- or post-emergence application in a directional or non-directionalfashion (e.g. by directional or non-directional spraying) at applicationrates between 1.0 kg and 20.0 kg, and preferably between 5.0 and 10.0kg, of active material per hectare are particularly suitable for thispurpose. When used to control the growth of weeds by pre-emergenceapplication, the compounds of formula (I) may be incorporated into thesoil in which the weeds are expected to emerge. It will be appreciatedthat when the compounds of formula (I) are used to control the growth ofweeds by post-emergence application, i.e. by application to the aerialor exposed portions of emerged weeds, the compounds of formula (I) willalso normally come into contact with the soil and may also then exercisea pre-emergence control on later-germinating weeds in the soil.

Where especially prolonged weed control is required, the application ofthe compounds of formula (I) may be repeated if required.

According to a further feature of the present invention, there areprovided compositions suitable for herbicidal use comprising one or moreof the isoxazole derivatives of formula (I) or agriculturally acceptablesalts thereof, in association with, and preferably homogeneouslydispersed in, one or more compatible agriculturally-acceptable diluentsor carriers and/or surface active agents [i.e. diluents or carriersand/or surface active agents of the type generally accepted in the artas being suitable for use in herbicidal compositions and which arecompatible with compounds of formula (I)]. The term “homogeneouslydispersed” is used to include compositions in which the compounds offormula (I) are dissolved in other components. The term “herbicidalcompositions” is used in a broad sense to include not only compositionswhich are ready for use as herbicides but also concentrates which mustbe diluted before use. Preferably, the compositions contain from 0.05 to90% by weight of one or more compounds of formula (I).

The herbicidal compositions may contain both a diluent or carrier andsurface-active (e.g. wetting, dispersing, or emulsifying) agent.Surface-active agents which may be present in herbicidal compositions ofthe present invention may be of the ionic or non-ionic types, forexample sulphoricinoleates, quaternary ammonium derivatives, productsbased on condensates of ethylene oxide with alkyl and polyaryl phenols,e.g. nonyl- or octyl-phenols, or carboxylic acid esters ofanhydrosorbitols which have been rendered soluble by etherification ofthe free hydroxy groups by condensation with ethylene oxide, alkali andalkaline earth metal salts of sulphuric acid esters and sulphonic acidssuch as dinonyl- and dioctyl-sodium sulphonosuccinates and alkali andalkaline earth metal salts of high molecular weight sulphonic acidderivatives such as sodium and calcium lignosulphonates and sodium andcalcium alkylbenzene sulphonates.

Suitably, the herbicidal compositions according to the present inventionmay comprise up to 10% by weight, e.g. from 0.05% to 10% by weight, ofsurface-active agent but, if desired, herbicidal compositions accordingto the present invention may comprise higher proportions ofsurface-active agent. for example up to 15% by weight in liquidemulsifiable suspension concentrates and up to 25% by weight in liquidwater soluble concentrates.

Examples of suitable solid diluents or carriers are aluminium silicate,talc, calcined magnesia, kieselguhr, tricalcium phosphate, powderedcork, absorbent carbon black and clays such as kaolin and bentonite. Thesolid compositions (which may take the form of dusts, granules orwettable powders) are preferably prepared by grinding the compounds offormula (I) with solid diluents or by impregnating the solid diluents orcarriers with solutions of the compounds of formula (I) in volatilesolvents, evaporating the solvents and, if necessary, grinding theproducts so as to obtain powders. Granular formulations may be preparedby absorbing the compounds of formula (I) (dissolved in suitablesolvents, which may, if desired, be volatile) onto the solid diluents orcarriers in granular form and, if desired, evaporating the solvents, orby granulating compositions in powder form obtained as described above.Solid herbicidal compositions, particularly wettable powders andgranules, may contain wetting or dispersing agents (for example of thetypes described above), which may also, when solid, serve as diluents orcarriers.

Liquid compositions according to the invention may take the form ofaqueous, organic or aqueous-organic solutions, suspensions and emulsionswhich may incorporate a surface-active agent. Suitable liquid diluentsfor incorporation in the liquid compositions include water, glycols,tetrahydrofurfuryl alcohol, acetophenone, cyclohexanone, isophorone,toluene, xylene, mineral, animal and vegetable oils and light aromaticand naphthenic fractions of petroleum (and mixtures of these diluents).Surface-active agents, which may be present in the liquid compositions,may be ionic or non-ionic (for example of the types described above) andmay, when liquid, also serve as diluents or carriers.

Powders, dispersible granules and liquid compositions in the form ofconcentrates may be diluted with water or other suitable diluents, forexample mineral or vegetable oils, particularly in the case of liquidconcentrates in which the diluent or carrier is an oil, to givecompositions ready for use.

When desired, liquid compositions of the compound of formula (I) may beused in the form of self-emulsifying concentrates containing the activesubstances dissolved in the emulsifying agents or in solvents containingemulsifying agents compatible with the active substances, the simpleaddition of water to such concentrates producing compositions ready foruse.

Liquid concentrates in which the diluent or carrier is an oil may beused without further dilution using the electrostatic spray technique.

Herbicidal compositions according to the present invention may alsocontain, if desired, conventional adjuvants such as adhesives,protective colloids, thickeners, penetrating agents, stabilisers,sequestering agents, anti-caking agents, colouring agents and corrosioninhibitors. These adjuvants may also serve as carriers or diluents.

Unless otherwise specified, the following percentages are by weight.Preferred herbicidal compositions according to the present invention are

aqueous suspension concentrates which comprise from 10 to 70% of one ormore compounds of formula (I), from 2 to 10% of surface-active agent,from 0.1 to 5% of thickener and from 15 to 87.9% of water,

wettable powders which comprise from 10 to 90% of one or more compoundsof formula (I), from 2 to 10% of surface-active agent and from 8 to 88%of solid diluent or carrier,

water soluble or water dispersible powders which comprise from 10 to 90%of one or more compounds of formula (I), from 2 to 40% of sodiumcarbonate and from 0 to 88% of solid diluent; liquid water solubleconcentrates which comprise from 5 to 50%, e.g. 10 to 30%, of one ormore compounds of formula (I), from 5 to 25% of surface-active agent andfrom 25 to 90%, e.g. 45 to 85%, of water miscible solvent, e.g.dimethylformamide, or a mixture of water-miscible solvent and water;

liquid emulsifiable suspension concentrates which comprise from 10 to70% of one or more compounds of formula (I), from 5 to 15% ofsurface-active agent, from 0.1 to 5% of thickener and from 10 to 84.9%of organic solvent;

granules which comprise from 1 to 90%, e.g. 2 to 10% of one or morecompounds of formula (I), from 0.5 to 7%, e.g. 0.5 to 2%, ofsurface-active agent and from 3 to 98.5%, e.g. 88 to 97.5%, of granularcarrier and

emulsifiable concentrates which comprise 0.05 to 90%, and preferablyfrom 1 to 60% of one or more compounds of formula (I), from 0.01 to 10%,and preferably from 1 to 10%, of surface-active agent and from 9.99 to99.94%, and preferably from 39 to 98.99%, of organic solvent.

Herbicidal compositions according to the present invention may alsocomprise the compounds of formula (I) in association with, andpreferably homogeneously dispersed in, one or more other pesticidallyactive compounds and, if desired, one or more compatible pesticidallyacceptable diluents or carriers, surface-active agents and conventionaladjuvants as hereinbefore described. Examples of other pesticidallyactive compounds which may be included in, or used in conjunction with,the herbicidal compositions of the present invention include herbicides,for example to increase the range of weed species controlled for examplealachlor[2-chloro-2,6′-diethyl-N-(methoxy-methyl)-acetanilide],atrazine[2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine],bromoxynil[3,5-dibromo-4-hydroxybenzonitrile],chlortoluron[N′-(3chloro-4-methylphenyl)-N,N-dimethylurea],cyanazine[2-chloro-4-(1cyano-1-methylethylamino)-6-ethylamino-1,3,5-triazine],2,4-D[2,4-dichlorophenoxy-acetic acid],dicamba[3,6-dichloro-2-methoxybenzoic acid],difenzoquat[1,2-dimethyl-3,5-diphenyl-pyrazolium salts],flampropmethyl[methylN-2-(N-benzoyl-3-chloro-4fluoroanilino)-propionate],fluometuron[N′-(3-trifluoromethylphenyl)-N,N-(dimethylurea],isoproturon[N′-(4-isopropylphenyl)-N,N-dimethylurea], insecticides, e.g.synthetic pyrethroids, e.g. permethrin and cypermethrin, and fungicides,e.g. carbamates, e.g. methyl N-(1-butyl-carbamoyl-benzimidazol-2-yl)carbamate, and triazoles e.g.1-(4-chloro-phenoxy)-3,3- dimethyl-1-(1,2,triazol-1-yl)-butan-2-one.

Pesticidally active compounds and other biologically active materialswhich may be included in, or used in conjunction with, the herbicidalcompositions of the present invention, for example those hereinbeforementioned, and which are acids, may, if desired, be utilized in the formof conventional derivatives, for example alkali metal and amine saltsand esters.

According to a further feature of the present invention there isprovided an article of manufacture comprising at least one isoxazolederivative of formula (I) or an agriculturally acceptable salt thereofor, as is preferred, a herbicidal composition as hereinbefore described,and preferably a herbicidal concentrate which must be diluted beforeuse, comprising at least one isoxazole derivative of formula (I) or anagriculturally acceptable salt thereof within a container for theaforesaid derivative or derivatives of formula (I), or a said herbicidalcomposition, and instructions physically associated with the aforesaidcontainer setting out the manner in which the aforesaid derivative orderivatives of formula (I) or herbicidal composition contained thereinis to be used to control the growth of weeds. The containers willnormally be of the types conventionally used for the storage of chemicalsubstances which are solid at normal ambient temperatures and herbicidalcompositions particularly in the form of concentrates, for example cansand drums of metal, which may be internally lacquered, and plasticsmaterials, bottles or glass and plastics materials and, when thecontents of the container is a solid, for example granular, herbicidalcompositions, boxes, for example of cardboard, plastics materials andmetal, or sacks. The containers will normally be of sufficient capacityto contain amounts of the isoxazole derivative or herbicidalcompositions sufficient to treat at least one acre of ground to controlthe growth of weeds therein but will not exceed a size which isconvenient for conventional methods of handling. The instructions willbe physically associated with the container, for example by beingprinted directly thereon or on a label or tag affixed thereto. Thedirections will normally indicate that the contents of the container,after dilution if necessary, are to be applied to control the growth ofweeds at rates of application between 0.01 kg and 20 kg of activematerial per hectare in the manner and for the purposes hereinbeforedescribed.

The following Examples illustrate herbicidal compositions according tothe present invention:

Example C1

A soluble concentrate is formed from:

Active ingredient (compound 1) 20% w/v Potassium hydroxide Solution 33%w/v 10% v/v Tetrahydrofurfuryl alcohol (THFA) 10% v/v Water to 100volumes.

by stirring THFA, active ingredient (compound 1) and 90% volume of waterand slowly adding the potassium hydroxide solution until a steady pH 7-8is obtained then making up to volume with water.

Similar soluble concentrates may be prepared as described above byreplacing the isoxazole (compound 1) with other compounds of formula(I).

Example C2

A wettable powder is formed from:

Active ingredient (compound 1) 50% w/w Sodium dodecylbenzene sulphonate 3% w/w Sodium lignosulphate  5% w/w Sodium formaldehydealkylnaphthalene sulphonate  2% w/w Microfine silicon dioxide  3% w/wand China clay 37% w/w

by blending the above ingredients together and grinding the mixture inan air jet mill.

Similar wettable powders may be prepared as described above by replacingthe isoxazole (compound 1) with other compounds of formula (I).

Example C3

A water soluble powder is formed from:

Active ingredient (compound 1) 50% w/w Sodium dodecylbenzenesulphonate 1% w/w Microfine silicon dioxide  2% w/w Sodium bicarbonate 47% w/w

by mixing the above ingredients and grinding the above mixture in ahammer mill.

Similar water soluble powders may be prepared as described above byreplacing the isoxazole (compound 1) with other compounds of formula(I).

The compounds of the invention have been used in herbicidal applicationsaccording to the following procedures.

Method of use of Herbicidal Compounds

a) General

Appropriate quantities of the compounds used to treat the plants weredissolved in acetone to give solutions equivalent to application ratesof up to 4000 g test compound per hectare (g/ha). These solutions wereapplied from a standard laboratory herbicide sprayer delivering theequivalent of 290 liters of spray fluid per hectare.

b) Weed control: Pre-emergence

The seeds were sown in 70 mm square, 75 mm deep plastic pots innon-sterile soil. The quantities of seed per pot were as follows:

Approx number of seeds/pot Weed species 1) Broad-leafed weeds Abutilontheophrasti 10 Amaranthus retroflexus 20 Galium aparine 10 Ipomoeapurpurea 10 Sinapis arvensis 15 Xanthium strumarium  2 2) Grass weedsAlopecurus myosuroides 15 Avena fatua 10 Echinochloa crus-galli 15Setaria viridis 20 3) Sedges Cyperus esculentus  3 Crop 1) Broad leafedCotton  3 Soya  3 2) Grass Maize  2 Rice  6 Wheat  6

The compounds of the invention were applied to the soil surface,containing the seeds, as described in (a). A single pot of each crop andeach weed was allocated to each treatment, with unsprayed controls andcontrols sprayed with acetone alone.

After treatment the pots were placed on capillary matting kept in aglass house, and watered overhead. Visual assessment of crop damage wasmade 20-24 days after spraying. The results were expressed as thepercentage reduction in growth or damage to the crop or weeds, incomparison with the plants in the control pots.

c) Weed control: Post-emergence

The weeds and crops were sown directly into John Innes potting compostin 75 mm deep, 70 mm square pots except for Amaranthus which was prickedout at the seedling stage and transferred to the pots one week beforespraying. The plants were then grown in the greenhouse until ready forspraying with the compounds used to treat the plants. The number ofplants per pot were as follows:

Number of plants per pot Growth stage Weed Species 1) Broad leafed weedsAbutilon theophrasti 3 1-2 leaves Amaranthus retroflexus 4 1-2 leavesGalium aparine 3 1^(st) whorl Ipomoea purpurea 3 1-2 leaves Sinapisarvensis 4 2 leaves Xanthium strumarium 1 2-3 leaves 2) Grass weedsAlopecurus myosuroides  8-12 1-2 leaves Avena fatua 12-18 1-2 leavesEchinochloa crus-galli 4 2-3 leaves Setaria viridis 15-25 1-2 leaves. 3)Sedges Cyperus esculentus 3 3 leaves. Crops 1) Broad leafed Cotton 2 1leaf Soya 2 2 leaves. 2) Grass Maize 2 2-3 leaves Rice 4 2-3 leavesWheat 5 2-3 leaves.

The compounds used to treat the plants were applied to the plants asdescribed in (a). A single pot of each crop and weed species wasallocated to each treatment, with unsprayed controls and controlssprayed with acetone alone.

After treatment the pots were placed on capillary matting in a glasshouse, and watered overhead once after 24 hours and then by controlledsub-irrigation. Visual assessment of crop damage and weed control wasmade 20-24 days after spraying. The results were expressed as thepercentage reduction in growth or damage to the crop or weeds, incomparison with the plants in the control pots.

The compounds of the invention, used at 4 kg/ha or less, have shown anexcellent level of herbicidal activity together with crop tolerance onthe weeds used in the foregoing experiments.

When applied pre- or post-emergence at 1000 g/ha or less compounds 1 to50 gave at least 90% reduction in growth of one or more of the weedspecies.

What is claimed is:
 1. A compound having the formula:

wherein: R² represents a halogen atom or a group selected from trifluoromethyl, methyl, C₁₋₂ haloalkoxy and S(O)_(p)CH₃ wherein p is zero, one or two; X represents —NR^(8′) wherein R^(8′) represents alkyl or alkenyl having up to four carbon atoms optionally substituted by one or more halogen atoms; n represents one or two; and R³ represents —C(Z)═Y wherein Y is oxygen, Z is R⁶³ or —OR⁶³, and R⁶³ represents alkyl having up to four carbon atoms.
 2. A compound according to claim 1 in which the 2-position of the benzene ring is substituted.
 3. A compound according to claim 1 in which the 5- and 6-positions of the benzene ring are unsubstituted.
 4. A compound according to claim 2 in which the 5- and 6-positions of the benzene ring are unsubstituted.
 5. A compound according to claim 1 in which R² represents halogen and R^(8′) represents an alkyl having up to four carbon atoms.
 6. A compound having the formula:

wherein: R² represents a halogen atom or a group selected from trifluoromethyl, methyl, C₁₋₂ haloalkoxy and S(O)_(p)CH₃ wherein p is zero, one or two; X represents —NR^(8′) wherein R^(8′) represents alkyl or alkenyl having up to four carbon atoms optionally substituted by one or more halogen atoms; n represents one or two; and R³ represents —C(Z)═Y wherein Y is oxygen, Z is R⁶³ or —OR⁶³, and R⁶³ represents alkyl having up to four carbon atoms optionally substituted by one or more halogen atoms; and wherein the compound is selected from the group consisting of: 3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-methyl-N-methoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-methyl-N-isopropyloxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-propyl-N-methoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-isopropyl-N-methoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-allyl-N-methoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-ethyl-N-propyloxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-ethyl-N-ethoxycarbonylamino)benzoic acid; 3,4-dichloro-2-(N-ethyl-N-isopropylcarbonylamino)benzoic acid; 3,4-dichloro-2-(N-ethyl-N-n-butyloxycarbonylamino)benzoic acid; and 4-bromo-2-(N-ethyl-N-methoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)benzoic acid. 